1gzl - Revision history

OCA at 06:29, 1 May 2024

OCA — Wed, 01 May 2024 06:29:11 GMT

←Older revision		Revision as of 06:29, 1 May 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[1gzl]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus Human immunodeficiency virus], [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] and [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GZL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1GZL FirstGlance]. <br>		<table><tr><td colspan='2'>[[1gzl]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus Human immunodeficiency virus], [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] and [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GZL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1GZL FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=N2P:PENTANE-1,5-DIAMINE'>N2P</scene></td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.8Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=N2P:PENTANE-1,5-DIAMINE'>N2P</scene></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1gzl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gzl OCA], [https://pdbe.org/1gzl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1gzl RCSB], [https://www.ebi.ac.uk/pdbsum/1gzl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1gzl ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1gzl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gzl OCA], [https://pdbe.org/1gzl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1gzl RCSB], [https://www.ebi.ac.uk/pdbsum/1gzl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1gzl ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/GCN4_YEAST GCN4_YEAST] Is a transcription factor that is responsible for the activation of more than 30 genes required for amino acid or for purine biosynthesis in response to amino acid or purine starvation. Binds and recognize the DNA sequence: 5'-TGA[CG]TCA-3'.[https://www.uniprot.org/uniprot/ENV_HV1H2 ENV_HV1H2] The surface protein gp120 (SU) attaches the virus to the host lymphoid cell by binding to the primary receptor CD4. This interaction induces a structural rearrangement creating a high affinity binding site for a chemokine coreceptor like CXCR4 and/or CCR5. This peculiar 2 stage receptor-interaction strategy allows gp120 to maintain the highly conserved coreceptor-binding site in a cryptic conformation, protected from neutralizing antibodies. Since CD4 also displays a binding site for the disulfide-isomerase P4HB/PDI, a P4HB/PDI-CD4-CXCR4-gp120 complex may form. In that complex, P4HB/PDI could reach and reduce gp120 disulfide bonds, causing major conformational changes in gp120. TXN, another PDI family member could also be involved in disulfide rearrangements in Env during fusion. These changes are transmitted to the transmembrane protein gp41 and are thought to activate its fusogenic potential by unmasking its fusion peptide.<ref>PMID:19410541</ref> Surface protein gp120 (SU) may target the virus to gut-associated lymphoid tissue (GALT) by binding host ITGA4/ITGB7 (alpha-4/beta-7 integrins), a complex that mediates T-cell migration to the GALT. Interaction between gp120 and ITGA4/ITGB7 would allow the virus to enter GALT early in the infection, infecting and killing most of GALT's resting CD4+ T-cells. This T-cell depletion is believed to be the major insult to the host immune system leading to AIDS (By similarity).<ref>PMID:19410541</ref> The surface protein gp120 is a ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on endothelial cells of liver sinusoids and lymph node sinuses. These interactions allow capture of viral particles at mucosal surfaces by these cells and subsequent transmission to permissive cells. DCs are professional antigen presenting cells, critical for host immunity by inducing specific immune responses against a broad variety of pathogens. They act as sentinels in various tissues where they take up antigen, process it, and present it to T-cells following migration to lymphoid organs. HIV subverts the migration properties of dendritic cells to gain access to CD4+ T-cells in lymph nodes. Virus transmission to permissive T-cells occurs either in trans (without DCs infection, through viral capture and transmission), or in cis (following DCs productive infection, through the usual CD4-gp120 interaction), thereby inducing a robust infection. In trans infection, bound virions remain infectious over days and it is proposed that they are not degraded, but protected in non-lysosomal acidic organelles within the DCs close to the cell membrane thus contributing to the viral infectious potential during DCs' migration from the periphery to the lymphoid tissues. On arrival at lymphoid tissues, intact virions recycle back to DCs' cell surface allowing virus transmission to CD4+ T-cells. Virion capture also seems to lead to MHC-II-restricted viral antigen presentation, and probably to the activation of HIV-specific CD4+ cells.<ref>PMID:19410541</ref> The transmembrane protein gp41 (TM) acts as a class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During fusion of viral and target intracellular membranes, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. Complete fusion occurs in host cell endosomes and is dynamin-dependent, however some lipid transfer might occur at the plasma membrane. The virus undergoes clathrin-dependent internalization long before endosomal fusion, thus minimizing the surface exposure of conserved viral epitopes during fusion and reducing the efficacy of inhibitors targeting these epitopes. Membranes fusion leads to delivery of the nucleocapsid into the cytoplasm.<ref>PMID:19410541</ref> The envelope glyprotein gp160 precursor down-modulates cell surface CD4 antigen by interacting with it in the endoplasmic reticulum and blocking its transport to the cell surface (By similarity).<ref>PMID:19410541</ref> The gp120-gp41 heterodimer seems to contribute to T-cell depletion during HIV-1 infection. The envelope glycoproteins expressed on the surface of infected cells induce apoptosis through an interaction with uninfected cells expressing the receptor (CD4) and the coreceptors CXCR4 or CCR5. This type of bystander killing may be obtained by at least three distinct mechanisms. First, the interaction between the 2 cells can induce cellular fusion followed by nuclear fusion within the syncytium. Syncytia are condemned to die from apoptosis. Second, the 2 interacting cells may not fuse entirely and simply exchange plasma membrane lipids, after a sort of hemifusion process, followed by rapid death. Third, it is possible that virus-infected cells, on the point of undergoing apoptosis, fuse with CD4-expressing cells, in which case apoptosis is rapidly transmitted from one cell to the other and thus occurs in a sort of contagious fashion.<ref>PMID:19410541</ref> The gp120-gp41 heterodimer allows rapid transcytosis of the virus through CD4 negative cells such as simple epithelial monolayers of the intestinal, rectal and endocervical epithelial barriers. Both gp120 and gp41 specifically recognize glycosphingolipids galactosyl-ceramide (GalCer) or 3' sulfo-galactosyl-ceramide (GalS) present in the lipid rafts structures of epithelial cells. Binding to these alternative receptors allows the rapid transcytosis of the virus through the epithelial cells. This transcytotic vesicle-mediated transport of virions from the apical side to the basolateral side of the epithelial cells does not involve infection of the cells themselves.<ref>PMID:19410541</ref>		[https://www.uniprot.org/uniprot/GCN4_YEAST GCN4_YEAST] Is a transcription factor that is responsible for the activation of more than 30 genes required for amino acid or for purine biosynthesis in response to amino acid or purine starvation. Binds and recognize the DNA sequence: 5'-TGA[CG]TCA-3'.[https://www.uniprot.org/uniprot/ENV_HV1H2 ENV_HV1H2] The surface protein gp120 (SU) attaches the virus to the host lymphoid cell by binding to the primary receptor CD4. This interaction induces a structural rearrangement creating a high affinity binding site for a chemokine coreceptor like CXCR4 and/or CCR5. This peculiar 2 stage receptor-interaction strategy allows gp120 to maintain the highly conserved coreceptor-binding site in a cryptic conformation, protected from neutralizing antibodies. Since CD4 also displays a binding site for the disulfide-isomerase P4HB/PDI, a P4HB/PDI-CD4-CXCR4-gp120 complex may form. In that complex, P4HB/PDI could reach and reduce gp120 disulfide bonds, causing major conformational changes in gp120. TXN, another PDI family member could also be involved in disulfide rearrangements in Env during fusion. These changes are transmitted to the transmembrane protein gp41 and are thought to activate its fusogenic potential by unmasking its fusion peptide.<ref>PMID:19410541</ref> Surface protein gp120 (SU) may target the virus to gut-associated lymphoid tissue (GALT) by binding host ITGA4/ITGB7 (alpha-4/beta-7 integrins), a complex that mediates T-cell migration to the GALT. Interaction between gp120 and ITGA4/ITGB7 would allow the virus to enter GALT early in the infection, infecting and killing most of GALT's resting CD4+ T-cells. This T-cell depletion is believed to be the major insult to the host immune system leading to AIDS (By similarity).<ref>PMID:19410541</ref> The surface protein gp120 is a ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on endothelial cells of liver sinusoids and lymph node sinuses. These interactions allow capture of viral particles at mucosal surfaces by these cells and subsequent transmission to permissive cells. DCs are professional antigen presenting cells, critical for host immunity by inducing specific immune responses against a broad variety of pathogens. They act as sentinels in various tissues where they take up antigen, process it, and present it to T-cells following migration to lymphoid organs. HIV subverts the migration properties of dendritic cells to gain access to CD4+ T-cells in lymph nodes. Virus transmission to permissive T-cells occurs either in trans (without DCs infection, through viral capture and transmission), or in cis (following DCs productive infection, through the usual CD4-gp120 interaction), thereby inducing a robust infection. In trans infection, bound virions remain infectious over days and it is proposed that they are not degraded, but protected in non-lysosomal acidic organelles within the DCs close to the cell membrane thus contributing to the viral infectious potential during DCs' migration from the periphery to the lymphoid tissues. On arrival at lymphoid tissues, intact virions recycle back to DCs' cell surface allowing virus transmission to CD4+ T-cells. Virion capture also seems to lead to MHC-II-restricted viral antigen presentation, and probably to the activation of HIV-specific CD4+ cells.<ref>PMID:19410541</ref> The transmembrane protein gp41 (TM) acts as a class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During fusion of viral and target intracellular membranes, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. Complete fusion occurs in host cell endosomes and is dynamin-dependent, however some lipid transfer might occur at the plasma membrane. The virus undergoes clathrin-dependent internalization long before endosomal fusion, thus minimizing the surface exposure of conserved viral epitopes during fusion and reducing the efficacy of inhibitors targeting these epitopes. Membranes fusion leads to delivery of the nucleocapsid into the cytoplasm.<ref>PMID:19410541</ref> The envelope glyprotein gp160 precursor down-modulates cell surface CD4 antigen by interacting with it in the endoplasmic reticulum and blocking its transport to the cell surface (By similarity).<ref>PMID:19410541</ref> The gp120-gp41 heterodimer seems to contribute to T-cell depletion during HIV-1 infection. The envelope glycoproteins expressed on the surface of infected cells induce apoptosis through an interaction with uninfected cells expressing the receptor (CD4) and the coreceptors CXCR4 or CCR5. This type of bystander killing may be obtained by at least three distinct mechanisms. First, the interaction between the 2 cells can induce cellular fusion followed by nuclear fusion within the syncytium. Syncytia are condemned to die from apoptosis. Second, the 2 interacting cells may not fuse entirely and simply exchange plasma membrane lipids, after a sort of hemifusion process, followed by rapid death. Third, it is possible that virus-infected cells, on the point of undergoing apoptosis, fuse with CD4-expressing cells, in which case apoptosis is rapidly transmitted from one cell to the other and thus occurs in a sort of contagious fashion.<ref>PMID:19410541</ref> The gp120-gp41 heterodimer allows rapid transcytosis of the virus through CD4 negative cells such as simple epithelial monolayers of the intestinal, rectal and endocervical epithelial barriers. Both gp120 and gp41 specifically recognize glycosphingolipids galactosyl-ceramide (GalCer) or 3' sulfo-galactosyl-ceramide (GalS) present in the lipid rafts structures of epithelial cells. Binding to these alternative receptors allows the rapid transcytosis of the virus through the epithelial cells. This transcytotic vesicle-mediated transport of virions from the apical side to the basolateral side of the epithelial cells does not involve infection of the cells themselves.<ref>PMID:19410541</ref>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	Peptides corresponding to the C-terminal heptad repeat of HIV-1 gp41 (C-peptides) are potent inhibitors of HIV-1 entry into cells. Their mechanism of inhibition involves binding in a helical conformation to the central coiled coil of HIV-1 gp41 in a dominant-negative manner. Short C-peptides, however, have low binding affinity for gp41 and poor inhibitory activity, which creates an obstacle to the development of small drug-like C-peptides. To improve the inhibitory potency of short C-peptides that target the hydrophobic pocket region of gp41, we use two strategies to stabilize the C-peptide helix: chemical crosslinking and substitution with unnatural helix-favoring amino acids. In this study, the short linear peptide shows no significant inhibitory activity, but a constrained peptide (C14linkmid) inhibits cell-cell fusion at micromolar potency. Structural studies confirm that the constrained peptides bind to the gp41 hydrophobic pocket. Calorimetry reveals that, of the peptides analyzed, the most potent are those that best balance the changes in binding enthalpy and entropy, and surprisingly not those with the highest helical propensity as measured by circular dichroism spectroscopy. Our study reveals the thermodynamic basis of inhibition of an HIV C-peptide, demonstrates the utility of constraining methods for a short antiviral peptide inhibitor, and has implications for the future design of constrained peptides.
-
-	Short constrained peptides that inhibit HIV-1 entry.,Sia SK, Carr PA, Cochran AG, Malashkevich VN, Kim PS Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14664-9. Epub 2002 Nov 4. PMID:12417739<ref>PMID:12417739</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 1gzl" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 06:04, 31 May 2023

OCA — Wed, 31 May 2023 06:04:32 GMT

←Older revision		Revision as of 06:04, 31 May 2023
Line 3:		Line 3:
	<StructureSection load='1gzl' size='340' side='right'caption='[[1gzl]], [[Resolution\|resolution]] 1.80Å' scene=''>		<StructureSection load='1gzl' size='340' side='right'caption='[[1gzl]], [[Resolution\|resolution]] 1.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[1gzl]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GZL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1GZL FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[1gzl]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus Human immunodeficiency virus], [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] and [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GZL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1GZL FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:~~CHLORIDE~~+~~ION~~'>CL</scene>, <scene name='pdbligand=~~N2P~~:~~PENTANE-1,5-DIAMINE~~'>~~N2P~~</scene>~~</td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=N2P:PENTANE-1,5-DIAMINE'>N2P</scene></td></tr>
-	~~<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat">~~<scene name='pdbligand=~~ACE~~:~~ACETYL+GROUP~~'>~~ACE~~</scene~~></td></tr>~~	+
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1dgc\|1dgc]], [[1e7t\|1e7t]], [[1env\|1env]], [[1fav\|1fav]], [[1gcl\|1gcl]], [[1gcm\|1gcm]], [[1gk6\|1gk6]], [[1ihq\|1ihq]], [[1ij0\|1ij0]], [[1ij1\|1ij1]], [[1ij2\|1ij2]], [[1ij3\|1ij3]], [[1kql\|1kql]], [[1piq\|1piq]], [[1swi\|1swi]], [[1tmz\|1tmz]], [[1ysa\|1ysa]], [[1zii\|1zii]], [[1zij\|1zij]], [[1zik\|1zik]], [[1zil\|1zil]], [[1zim\|1zim]], [[1zta\|1zta]], [[2dgc\|2dgc]], [[2zta\|2zta]]</div></td></tr>	+
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1gzl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gzl OCA], [https://pdbe.org/1gzl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1gzl RCSB], [https://www.ebi.ac.uk/pdbsum/1gzl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1gzl ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1gzl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gzl OCA], [https://pdbe.org/1gzl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1gzl RCSB], [https://www.ebi.ac.uk/pdbsum/1gzl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1gzl ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/ENV_HV1H2 ENV_HV1H2]] The surface protein gp120 (SU) attaches the virus to the host lymphoid cell by binding to the primary receptor CD4. This interaction induces a structural rearrangement creating a high affinity binding site for a chemokine coreceptor like CXCR4 and/or CCR5. This peculiar 2 stage receptor-interaction strategy allows gp120 to maintain the highly conserved coreceptor-binding site in a cryptic conformation, protected from neutralizing antibodies. Since CD4 also displays a binding site for the disulfide-isomerase P4HB/PDI, a P4HB/PDI-CD4-CXCR4-gp120 complex may form. In that complex, P4HB/PDI could reach and reduce gp120 disulfide bonds, causing major conformational changes in gp120. TXN, another PDI family member could also be involved in disulfide rearrangements in Env during fusion. These changes are transmitted to the transmembrane protein gp41 and are thought to activate its fusogenic potential by unmasking its fusion peptide.<ref>PMID:19410541</ref> Surface protein gp120 (SU) may target the virus to gut-associated lymphoid tissue (GALT) by binding host ITGA4/ITGB7 (alpha-4/beta-7 integrins), a complex that mediates T-cell migration to the GALT. Interaction between gp120 and ITGA4/ITGB7 would allow the virus to enter GALT early in the infection, infecting and killing most of GALT's resting CD4+ T-cells. This T-cell depletion is believed to be the major insult to the host immune system leading to AIDS (By similarity).<ref>PMID:19410541</ref> The surface protein gp120 is a ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on endothelial cells of liver sinusoids and lymph node sinuses. These interactions allow capture of viral particles at mucosal surfaces by these cells and subsequent transmission to permissive cells. DCs are professional antigen presenting cells, critical for host immunity by inducing specific immune responses against a broad variety of pathogens. They act as sentinels in various tissues where they take up antigen, process it, and present it to T-cells following migration to lymphoid organs. HIV subverts the migration properties of dendritic cells to gain access to CD4+ T-cells in lymph nodes. Virus transmission to permissive T-cells occurs either in trans (without DCs infection, through viral capture and transmission), or in cis (following DCs productive infection, through the usual CD4-gp120 interaction), thereby inducing a robust infection. In trans infection, bound virions remain infectious over days and it is proposed that they are not degraded, but protected in non-lysosomal acidic organelles within the DCs close to the cell membrane thus contributing to the viral infectious potential during DCs' migration from the periphery to the lymphoid tissues. On arrival at lymphoid tissues, intact virions recycle back to DCs' cell surface allowing virus transmission to CD4+ T-cells. Virion capture also seems to lead to MHC-II-restricted viral antigen presentation, and probably to the activation of HIV-specific CD4+ cells.<ref>PMID:19410541</ref> The transmembrane protein gp41 (TM) acts as a class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During fusion of viral and target intracellular membranes, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. Complete fusion occurs in host cell endosomes and is dynamin-dependent, however some lipid transfer might occur at the plasma membrane. The virus undergoes clathrin-dependent internalization long before endosomal fusion, thus minimizing the surface exposure of conserved viral epitopes during fusion and reducing the efficacy of inhibitors targeting these epitopes. Membranes fusion leads to delivery of the nucleocapsid into the cytoplasm.<ref>PMID:19410541</ref> The envelope glyprotein gp160 precursor down-modulates cell surface CD4 antigen by interacting with it in the endoplasmic reticulum and blocking its transport to the cell surface (By similarity).<ref>PMID:19410541</ref> The gp120-gp41 heterodimer seems to contribute to T-cell depletion during HIV-1 infection. The envelope glycoproteins expressed on the surface of infected cells induce apoptosis through an interaction with uninfected cells expressing the receptor (CD4) and the coreceptors CXCR4 or CCR5. This type of bystander killing may be obtained by at least three distinct mechanisms. First, the interaction between the 2 cells can induce cellular fusion followed by nuclear fusion within the syncytium. Syncytia are condemned to die from apoptosis. Second, the 2 interacting cells may not fuse entirely and simply exchange plasma membrane lipids, after a sort of hemifusion process, followed by rapid death. Third, it is possible that virus-infected cells, on the point of undergoing apoptosis, fuse with CD4-expressing cells, in which case apoptosis is rapidly transmitted from one cell to the other and thus occurs in a sort of contagious fashion.<ref>PMID:19410541</ref> The gp120-gp41 heterodimer allows rapid transcytosis of the virus through CD4 negative cells such as simple epithelial monolayers of the intestinal, rectal and endocervical epithelial barriers. Both gp120 and gp41 specifically recognize glycosphingolipids galactosyl-ceramide (GalCer) or 3' sulfo-galactosyl-ceramide (GalS) present in the lipid rafts structures of epithelial cells. Binding to these alternative receptors allows the rapid transcytosis of the virus through the epithelial cells. This transcytotic vesicle-mediated transport of virions from the apical side to the basolateral side of the epithelial cells does not involve infection of the cells themselves.<ref>PMID:19410541</ref>	+	[https://www.uniprot.org/uniprot/GCN4_YEAST GCN4_YEAST] Is a transcription factor that is responsible for the activation of more than 30 genes required for amino acid or for purine biosynthesis in response to amino acid or purine starvation. Binds and recognize the DNA sequence: 5'-TGA[CG]TCA-3'.[https://www.uniprot.org/uniprot/ENV_HV1H2 ENV_HV1H2] The surface protein gp120 (SU) attaches the virus to the host lymphoid cell by binding to the primary receptor CD4. This interaction induces a structural rearrangement creating a high affinity binding site for a chemokine coreceptor like CXCR4 and/or CCR5. This peculiar 2 stage receptor-interaction strategy allows gp120 to maintain the highly conserved coreceptor-binding site in a cryptic conformation, protected from neutralizing antibodies. Since CD4 also displays a binding site for the disulfide-isomerase P4HB/PDI, a P4HB/PDI-CD4-CXCR4-gp120 complex may form. In that complex, P4HB/PDI could reach and reduce gp120 disulfide bonds, causing major conformational changes in gp120. TXN, another PDI family member could also be involved in disulfide rearrangements in Env during fusion. These changes are transmitted to the transmembrane protein gp41 and are thought to activate its fusogenic potential by unmasking its fusion peptide.<ref>PMID:19410541</ref> Surface protein gp120 (SU) may target the virus to gut-associated lymphoid tissue (GALT) by binding host ITGA4/ITGB7 (alpha-4/beta-7 integrins), a complex that mediates T-cell migration to the GALT. Interaction between gp120 and ITGA4/ITGB7 would allow the virus to enter GALT early in the infection, infecting and killing most of GALT's resting CD4+ T-cells. This T-cell depletion is believed to be the major insult to the host immune system leading to AIDS (By similarity).<ref>PMID:19410541</ref> The surface protein gp120 is a ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on endothelial cells of liver sinusoids and lymph node sinuses. These interactions allow capture of viral particles at mucosal surfaces by these cells and subsequent transmission to permissive cells. DCs are professional antigen presenting cells, critical for host immunity by inducing specific immune responses against a broad variety of pathogens. They act as sentinels in various tissues where they take up antigen, process it, and present it to T-cells following migration to lymphoid organs. HIV subverts the migration properties of dendritic cells to gain access to CD4+ T-cells in lymph nodes. Virus transmission to permissive T-cells occurs either in trans (without DCs infection, through viral capture and transmission), or in cis (following DCs productive infection, through the usual CD4-gp120 interaction), thereby inducing a robust infection. In trans infection, bound virions remain infectious over days and it is proposed that they are not degraded, but protected in non-lysosomal acidic organelles within the DCs close to the cell membrane thus contributing to the viral infectious potential during DCs' migration from the periphery to the lymphoid tissues. On arrival at lymphoid tissues, intact virions recycle back to DCs' cell surface allowing virus transmission to CD4+ T-cells. Virion capture also seems to lead to MHC-II-restricted viral antigen presentation, and probably to the activation of HIV-specific CD4+ cells.<ref>PMID:19410541</ref> The transmembrane protein gp41 (TM) acts as a class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During fusion of viral and target intracellular membranes, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. Complete fusion occurs in host cell endosomes and is dynamin-dependent, however some lipid transfer might occur at the plasma membrane. The virus undergoes clathrin-dependent internalization long before endosomal fusion, thus minimizing the surface exposure of conserved viral epitopes during fusion and reducing the efficacy of inhibitors targeting these epitopes. Membranes fusion leads to delivery of the nucleocapsid into the cytoplasm.<ref>PMID:19410541</ref> The envelope glyprotein gp160 precursor down-modulates cell surface CD4 antigen by interacting with it in the endoplasmic reticulum and blocking its transport to the cell surface (By similarity).<ref>PMID:19410541</ref> The gp120-gp41 heterodimer seems to contribute to T-cell depletion during HIV-1 infection. The envelope glycoproteins expressed on the surface of infected cells induce apoptosis through an interaction with uninfected cells expressing the receptor (CD4) and the coreceptors CXCR4 or CCR5. This type of bystander killing may be obtained by at least three distinct mechanisms. First, the interaction between the 2 cells can induce cellular fusion followed by nuclear fusion within the syncytium. Syncytia are condemned to die from apoptosis. Second, the 2 interacting cells may not fuse entirely and simply exchange plasma membrane lipids, after a sort of hemifusion process, followed by rapid death. Third, it is possible that virus-infected cells, on the point of undergoing apoptosis, fuse with CD4-expressing cells, in which case apoptosis is rapidly transmitted from one cell to the other and thus occurs in a sort of contagious fashion.<ref>PMID:19410541</ref> The gp120-gp41 heterodimer allows rapid transcytosis of the virus through CD4 negative cells such as simple epithelial monolayers of the intestinal, rectal and endocervical epithelial barriers. Both gp120 and gp41 specifically recognize glycosphingolipids galactosyl-ceramide (GalCer) or 3' sulfo-galactosyl-ceramide (GalS) present in the lipid rafts structures of epithelial cells. Binding to these alternative receptors allows the rapid transcytosis of the virus through the epithelial cells. This transcytotic vesicle-mediated transport of virions from the apical side to the basolateral side of the epithelial cells does not involve infection of the cells themselves.<ref>PMID:19410541</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 24:		Line 22:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human immunodeficiency virus]]
		+	[[Category: Human immunodeficiency virus 1]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Carr, P A~~]]	+	[[Category: Saccharomyces cerevisiae]]
-	[[Category: ~~Cochran, A G~~]]	+	[[Category: Carr PA]]
-	[[Category: ~~Kim, P S~~]]	+	[[Category: Cochran AG]]
-	[[Category: ~~Malashkevich, V M~~]]	+	[[Category: Kim PS]]
-	[[Category: ~~Sia, S K~~]]	+	[[Category: Malashkevich VM]]
-	[[Category: ~~Coiled coil]]~~	+	[[Category: Sia SK]]
-	~~[[Category: Cross-link]]~~	+
-	~~[[Category: Glycoprotein]]~~	+
-	~~[[Category: Gp41]]~~	+
-	~~[[Category: Hiv entry]]~~	+
-	~~[[Category: Inhibitor~~]]	+

OCA at 06:49, 25 August 2021

OCA — Wed, 25 Aug 2021 06:49:23 GMT

←Older revision		Revision as of 06:49, 25 August 2021
Line 3:		Line 3:
	<StructureSection load='1gzl' size='340' side='right'caption='[[1gzl]], [[Resolution\|resolution]] 1.80Å' scene=''>		<StructureSection load='1gzl' size='340' side='right'caption='[[1gzl]], [[Resolution\|resolution]] 1.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[1gzl]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GZL OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=1GZL FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[1gzl]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GZL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1GZL FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=N2P:PENTANE-1,5-DIAMINE'>N2P</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=N2P:PENTANE-1,5-DIAMINE'>N2P</scene></td></tr>
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1dgc\|1dgc]], [[1e7t\|1e7t]], [[1env\|1env]], [[1fav\|1fav]], [[1gcl\|1gcl]], [[1gcm\|1gcm]], [[1gk6\|1gk6]], [[1ihq\|1ihq]], [[1ij0\|1ij0]], [[1ij1\|1ij1]], [[1ij2\|1ij2]], [[1ij3\|1ij3]], [[1kql\|1kql]], [[1piq\|1piq]], [[1swi\|1swi]], [[1tmz\|1tmz]], [[1ysa\|1ysa]], [[1zii\|1zii]], [[1zij\|1zij]], [[1zik\|1zik]], [[1zil\|1zil]], [[1zim\|1zim]], [[1zta\|1zta]], [[2dgc\|2dgc]], [[2zta\|2zta]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1dgc\|1dgc]], [[1e7t\|1e7t]], [[1env\|1env]], [[1fav\|1fav]], [[1gcl\|1gcl]], [[1gcm\|1gcm]], [[1gk6\|1gk6]], [[1ihq\|1ihq]], [[1ij0\|1ij0]], [[1ij1\|1ij1]], [[1ij2\|1ij2]], [[1ij3\|1ij3]], [[1kql\|1kql]], [[1piq\|1piq]], [[1swi\|1swi]], [[1tmz\|1tmz]], [[1ysa\|1ysa]], [[1zii\|1zii]], [[1zij\|1zij]], [[1zik\|1zik]], [[1zil\|1zil]], [[1zim\|1zim]], [[1zta\|1zta]], [[2dgc\|2dgc]], [[2zta\|2zta]]</div></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=1gzl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gzl OCA], [~~http~~://pdbe.org/1gzl PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=1gzl RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/1gzl PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=1gzl ProSAT]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1gzl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gzl OCA], [https://pdbe.org/1gzl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1gzl RCSB], [https://www.ebi.ac.uk/pdbsum/1gzl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1gzl ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/ENV_HV1H2 ENV_HV1H2]] The surface protein gp120 (SU) attaches the virus to the host lymphoid cell by binding to the primary receptor CD4. This interaction induces a structural rearrangement creating a high affinity binding site for a chemokine coreceptor like CXCR4 and/or CCR5. This peculiar 2 stage receptor-interaction strategy allows gp120 to maintain the highly conserved coreceptor-binding site in a cryptic conformation, protected from neutralizing antibodies. Since CD4 also displays a binding site for the disulfide-isomerase P4HB/PDI, a P4HB/PDI-CD4-CXCR4-gp120 complex may form. In that complex, P4HB/PDI could reach and reduce gp120 disulfide bonds, causing major conformational changes in gp120. TXN, another PDI family member could also be involved in disulfide rearrangements in Env during fusion. These changes are transmitted to the transmembrane protein gp41 and are thought to activate its fusogenic potential by unmasking its fusion peptide.<ref>PMID:19410541</ref> Surface protein gp120 (SU) may target the virus to gut-associated lymphoid tissue (GALT) by binding host ITGA4/ITGB7 (alpha-4/beta-7 integrins), a complex that mediates T-cell migration to the GALT. Interaction between gp120 and ITGA4/ITGB7 would allow the virus to enter GALT early in the infection, infecting and killing most of GALT's resting CD4+ T-cells. This T-cell depletion is believed to be the major insult to the host immune system leading to AIDS (By similarity).<ref>PMID:19410541</ref> The surface protein gp120 is a ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on endothelial cells of liver sinusoids and lymph node sinuses. These interactions allow capture of viral particles at mucosal surfaces by these cells and subsequent transmission to permissive cells. DCs are professional antigen presenting cells, critical for host immunity by inducing specific immune responses against a broad variety of pathogens. They act as sentinels in various tissues where they take up antigen, process it, and present it to T-cells following migration to lymphoid organs. HIV subverts the migration properties of dendritic cells to gain access to CD4+ T-cells in lymph nodes. Virus transmission to permissive T-cells occurs either in trans (without DCs infection, through viral capture and transmission), or in cis (following DCs productive infection, through the usual CD4-gp120 interaction), thereby inducing a robust infection. In trans infection, bound virions remain infectious over days and it is proposed that they are not degraded, but protected in non-lysosomal acidic organelles within the DCs close to the cell membrane thus contributing to the viral infectious potential during DCs' migration from the periphery to the lymphoid tissues. On arrival at lymphoid tissues, intact virions recycle back to DCs' cell surface allowing virus transmission to CD4+ T-cells. Virion capture also seems to lead to MHC-II-restricted viral antigen presentation, and probably to the activation of HIV-specific CD4+ cells.<ref>PMID:19410541</ref> The transmembrane protein gp41 (TM) acts as a class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During fusion of viral and target intracellular membranes, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. Complete fusion occurs in host cell endosomes and is dynamin-dependent, however some lipid transfer might occur at the plasma membrane. The virus undergoes clathrin-dependent internalization long before endosomal fusion, thus minimizing the surface exposure of conserved viral epitopes during fusion and reducing the efficacy of inhibitors targeting these epitopes. Membranes fusion leads to delivery of the nucleocapsid into the cytoplasm.<ref>PMID:19410541</ref> The envelope glyprotein gp160 precursor down-modulates cell surface CD4 antigen by interacting with it in the endoplasmic reticulum and blocking its transport to the cell surface (By similarity).<ref>PMID:19410541</ref> The gp120-gp41 heterodimer seems to contribute to T-cell depletion during HIV-1 infection. The envelope glycoproteins expressed on the surface of infected cells induce apoptosis through an interaction with uninfected cells expressing the receptor (CD4) and the coreceptors CXCR4 or CCR5. This type of bystander killing may be obtained by at least three distinct mechanisms. First, the interaction between the 2 cells can induce cellular fusion followed by nuclear fusion within the syncytium. Syncytia are condemned to die from apoptosis. Second, the 2 interacting cells may not fuse entirely and simply exchange plasma membrane lipids, after a sort of hemifusion process, followed by rapid death. Third, it is possible that virus-infected cells, on the point of undergoing apoptosis, fuse with CD4-expressing cells, in which case apoptosis is rapidly transmitted from one cell to the other and thus occurs in a sort of contagious fashion.<ref>PMID:19410541</ref> The gp120-gp41 heterodimer allows rapid transcytosis of the virus through CD4 negative cells such as simple epithelial monolayers of the intestinal, rectal and endocervical epithelial barriers. Both gp120 and gp41 specifically recognize glycosphingolipids galactosyl-ceramide (GalCer) or 3' sulfo-galactosyl-ceramide (GalS) present in the lipid rafts structures of epithelial cells. Binding to these alternative receptors allows the rapid transcytosis of the virus through the epithelial cells. This transcytotic vesicle-mediated transport of virions from the apical side to the basolateral side of the epithelial cells does not involve infection of the cells themselves.<ref>PMID:19410541</ref>	+	[[https://www.uniprot.org/uniprot/ENV_HV1H2 ENV_HV1H2]] The surface protein gp120 (SU) attaches the virus to the host lymphoid cell by binding to the primary receptor CD4. This interaction induces a structural rearrangement creating a high affinity binding site for a chemokine coreceptor like CXCR4 and/or CCR5. This peculiar 2 stage receptor-interaction strategy allows gp120 to maintain the highly conserved coreceptor-binding site in a cryptic conformation, protected from neutralizing antibodies. Since CD4 also displays a binding site for the disulfide-isomerase P4HB/PDI, a P4HB/PDI-CD4-CXCR4-gp120 complex may form. In that complex, P4HB/PDI could reach and reduce gp120 disulfide bonds, causing major conformational changes in gp120. TXN, another PDI family member could also be involved in disulfide rearrangements in Env during fusion. These changes are transmitted to the transmembrane protein gp41 and are thought to activate its fusogenic potential by unmasking its fusion peptide.<ref>PMID:19410541</ref> Surface protein gp120 (SU) may target the virus to gut-associated lymphoid tissue (GALT) by binding host ITGA4/ITGB7 (alpha-4/beta-7 integrins), a complex that mediates T-cell migration to the GALT. Interaction between gp120 and ITGA4/ITGB7 would allow the virus to enter GALT early in the infection, infecting and killing most of GALT's resting CD4+ T-cells. This T-cell depletion is believed to be the major insult to the host immune system leading to AIDS (By similarity).<ref>PMID:19410541</ref> The surface protein gp120 is a ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on endothelial cells of liver sinusoids and lymph node sinuses. These interactions allow capture of viral particles at mucosal surfaces by these cells and subsequent transmission to permissive cells. DCs are professional antigen presenting cells, critical for host immunity by inducing specific immune responses against a broad variety of pathogens. They act as sentinels in various tissues where they take up antigen, process it, and present it to T-cells following migration to lymphoid organs. HIV subverts the migration properties of dendritic cells to gain access to CD4+ T-cells in lymph nodes. Virus transmission to permissive T-cells occurs either in trans (without DCs infection, through viral capture and transmission), or in cis (following DCs productive infection, through the usual CD4-gp120 interaction), thereby inducing a robust infection. In trans infection, bound virions remain infectious over days and it is proposed that they are not degraded, but protected in non-lysosomal acidic organelles within the DCs close to the cell membrane thus contributing to the viral infectious potential during DCs' migration from the periphery to the lymphoid tissues. On arrival at lymphoid tissues, intact virions recycle back to DCs' cell surface allowing virus transmission to CD4+ T-cells. Virion capture also seems to lead to MHC-II-restricted viral antigen presentation, and probably to the activation of HIV-specific CD4+ cells.<ref>PMID:19410541</ref> The transmembrane protein gp41 (TM) acts as a class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During fusion of viral and target intracellular membranes, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. Complete fusion occurs in host cell endosomes and is dynamin-dependent, however some lipid transfer might occur at the plasma membrane. The virus undergoes clathrin-dependent internalization long before endosomal fusion, thus minimizing the surface exposure of conserved viral epitopes during fusion and reducing the efficacy of inhibitors targeting these epitopes. Membranes fusion leads to delivery of the nucleocapsid into the cytoplasm.<ref>PMID:19410541</ref> The envelope glyprotein gp160 precursor down-modulates cell surface CD4 antigen by interacting with it in the endoplasmic reticulum and blocking its transport to the cell surface (By similarity).<ref>PMID:19410541</ref> The gp120-gp41 heterodimer seems to contribute to T-cell depletion during HIV-1 infection. The envelope glycoproteins expressed on the surface of infected cells induce apoptosis through an interaction with uninfected cells expressing the receptor (CD4) and the coreceptors CXCR4 or CCR5. This type of bystander killing may be obtained by at least three distinct mechanisms. First, the interaction between the 2 cells can induce cellular fusion followed by nuclear fusion within the syncytium. Syncytia are condemned to die from apoptosis. Second, the 2 interacting cells may not fuse entirely and simply exchange plasma membrane lipids, after a sort of hemifusion process, followed by rapid death. Third, it is possible that virus-infected cells, on the point of undergoing apoptosis, fuse with CD4-expressing cells, in which case apoptosis is rapidly transmitted from one cell to the other and thus occurs in a sort of contagious fashion.<ref>PMID:19410541</ref> The gp120-gp41 heterodimer allows rapid transcytosis of the virus through CD4 negative cells such as simple epithelial monolayers of the intestinal, rectal and endocervical epithelial barriers. Both gp120 and gp41 specifically recognize glycosphingolipids galactosyl-ceramide (GalCer) or 3' sulfo-galactosyl-ceramide (GalS) present in the lipid rafts structures of epithelial cells. Binding to these alternative receptors allows the rapid transcytosis of the virus through the epithelial cells. This transcytotic vesicle-mediated transport of virions from the apical side to the basolateral side of the epithelial cells does not involve infection of the cells themselves.<ref>PMID:19410541</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==

OCA at 08:33, 26 June 2019

OCA — Wed, 26 Jun 2019 08:33:51 GMT

←Older revision		Revision as of 08:33, 26 June 2019
Line 1:		Line 1:

	==Crystal structure of C14linkmid/IQN17: a cross-linked inhibitor of HIV-1 entry bound to the gp41 hydrophobic pocket==		==Crystal structure of C14linkmid/IQN17: a cross-linked inhibitor of HIV-1 entry bound to the gp41 hydrophobic pocket==
-	<StructureSection load='1gzl' size='340' side='right' caption='[[1gzl]], [[Resolution\|resolution]] 1.80Å' scene=''>	+	<StructureSection load='1gzl' size='340' side='right'caption='[[1gzl]], [[Resolution\|resolution]] 1.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[1gzl]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GZL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1GZL FirstGlance]. <br>		<table><tr><td colspan='2'>[[1gzl]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GZL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1GZL FirstGlance]. <br>
Line 24:		Line 24:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Carr, P A]]		[[Category: Carr, P A]]
	[[Category: Cochran, A G]]		[[Category: Cochran, A G]]

OCA at 04:34, 21 September 2017

OCA — Thu, 21 Sep 2017 04:34:16 GMT

←Older revision		Revision as of 04:34, 21 September 2017
Line 1:		Line 1:
		+
	==Crystal structure of C14linkmid/IQN17: a cross-linked inhibitor of HIV-1 entry bound to the gp41 hydrophobic pocket==		==Crystal structure of C14linkmid/IQN17: a cross-linked inhibitor of HIV-1 entry bound to the gp41 hydrophobic pocket==
	<StructureSection load='1gzl' size='340' side='right' caption='[[1gzl]], [[Resolution\|resolution]] 1.80Å' scene=''>		<StructureSection load='1gzl' size='340' side='right' caption='[[1gzl]], [[Resolution\|resolution]] 1.80Å' scene=''>
Line 6:		Line 7:
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1dgc\|1dgc]], [[1e7t\|1e7t]], [[1env\|1env]], [[1fav\|1fav]], [[1gcl\|1gcl]], [[1gcm\|1gcm]], [[1gk6\|1gk6]], [[1ihq\|1ihq]], [[1ij0\|1ij0]], [[1ij1\|1ij1]], [[1ij2\|1ij2]], [[1ij3\|1ij3]], [[1kql\|1kql]], [[1piq\|1piq]], [[1swi\|1swi]], [[1tmz\|1tmz]], [[1ysa\|1ysa]], [[1zii\|1zii]], [[1zij\|1zij]], [[1zik\|1zik]], [[1zil\|1zil]], [[1zim\|1zim]], [[1zta\|1zta]], [[2dgc\|2dgc]], [[2zta\|2zta]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1dgc\|1dgc]], [[1e7t\|1e7t]], [[1env\|1env]], [[1fav\|1fav]], [[1gcl\|1gcl]], [[1gcm\|1gcm]], [[1gk6\|1gk6]], [[1ihq\|1ihq]], [[1ij0\|1ij0]], [[1ij1\|1ij1]], [[1ij2\|1ij2]], [[1ij3\|1ij3]], [[1kql\|1kql]], [[1piq\|1piq]], [[1swi\|1swi]], [[1tmz\|1tmz]], [[1ysa\|1ysa]], [[1zii\|1zii]], [[1zij\|1zij]], [[1zik\|1zik]], [[1zil\|1zil]], [[1zim\|1zim]], [[1zta\|1zta]], [[2dgc\|2dgc]], [[2zta\|2zta]]</td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1gzl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gzl OCA], [http://pdbe.org/1gzl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1gzl RCSB], [http://www.ebi.ac.uk/pdbsum/1gzl PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1gzl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gzl OCA], [http://pdbe.org/1gzl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1gzl RCSB], [http://www.ebi.ac.uk/pdbsum/1gzl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1gzl ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 28:		Line 29:
	[[Category: Malashkevich, V M]]		[[Category: Malashkevich, V M]]
	[[Category: Sia, S K]]		[[Category: Sia, S K]]
		+	[[Category: Coiled coil]]
	[[Category: Cross-link]]		[[Category: Cross-link]]
	[[Category: Glycoprotein]]		[[Category: Glycoprotein]]

OCA at 10:08, 2 December 2015

OCA — Wed, 02 Dec 2015 10:08:53 GMT

←Older revision		Revision as of 10:08, 2 December 2015
Line 1:		Line 1:
-	==~~CRYSTAL STRUCTURE OF C14LINKMID~~/IQN17: ~~A CROSS~~-~~LINKED INHIBITOR OF~~ HIV-1 ~~ENTRY BOUND TO THE GP41 HYDROPHOBIC POCKET~~==	+	==Crystal structure of C14linkmid/IQN17: a cross-linked inhibitor of HIV-1 entry bound to the gp41 hydrophobic pocket==
	<StructureSection load='1gzl' size='340' side='right' caption='[[1gzl]], [[Resolution\|resolution]] 1.80Å' scene=''>		<StructureSection load='1gzl' size='340' side='right' caption='[[1gzl]], [[Resolution\|resolution]] 1.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==

OCA at 08:47, 10 September 2015

OCA — Thu, 10 Sep 2015 08:47:13 GMT

←Older revision		Revision as of 08:47, 10 September 2015
Line 6:		Line 6:
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1dgc\|1dgc]], [[1e7t\|1e7t]], [[1env\|1env]], [[1fav\|1fav]], [[1gcl\|1gcl]], [[1gcm\|1gcm]], [[1gk6\|1gk6]], [[1ihq\|1ihq]], [[1ij0\|1ij0]], [[1ij1\|1ij1]], [[1ij2\|1ij2]], [[1ij3\|1ij3]], [[1kql\|1kql]], [[1piq\|1piq]], [[1swi\|1swi]], [[1tmz\|1tmz]], [[1ysa\|1ysa]], [[1zii\|1zii]], [[1zij\|1zij]], [[1zik\|1zik]], [[1zil\|1zil]], [[1zim\|1zim]], [[1zta\|1zta]], [[2dgc\|2dgc]], [[2zta\|2zta]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1dgc\|1dgc]], [[1e7t\|1e7t]], [[1env\|1env]], [[1fav\|1fav]], [[1gcl\|1gcl]], [[1gcm\|1gcm]], [[1gk6\|1gk6]], [[1ihq\|1ihq]], [[1ij0\|1ij0]], [[1ij1\|1ij1]], [[1ij2\|1ij2]], [[1ij3\|1ij3]], [[1kql\|1kql]], [[1piq\|1piq]], [[1swi\|1swi]], [[1tmz\|1tmz]], [[1ysa\|1ysa]], [[1zii\|1zii]], [[1zij\|1zij]], [[1zik\|1zik]], [[1zil\|1zil]], [[1zim\|1zim]], [[1zta\|1zta]], [[2dgc\|2dgc]], [[2zta\|2zta]]</td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1gzl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gzl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1gzl RCSB], [http://www.ebi.ac.uk/pdbsum/1gzl PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1gzl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gzl OCA], [http://pdbe.org/1gzl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1gzl RCSB], [http://www.ebi.ac.uk/pdbsum/1gzl PDBsum]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 18:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 1gzl" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 21:18, 24 December 2014

OCA — Wed, 24 Dec 2014 21:18:20 GMT

←Older revision		Revision as of 21:18, 24 December 2014
Line 8:		Line 8:
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1gzl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gzl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1gzl RCSB], [http://www.ebi.ac.uk/pdbsum/1gzl PDBsum]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1gzl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gzl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1gzl RCSB], [http://www.ebi.ac.uk/pdbsum/1gzl PDBsum]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/ENV_HV1H2 ENV_HV1H2]] The surface protein gp120 (SU) attaches the virus to the host lymphoid cell by binding to the primary receptor CD4. This interaction induces a structural rearrangement creating a high affinity binding site for a chemokine coreceptor like CXCR4 and/or CCR5. This peculiar 2 stage receptor-interaction strategy allows gp120 to maintain the highly conserved coreceptor-binding site in a cryptic conformation, protected from neutralizing antibodies. Since CD4 also displays a binding site for the disulfide-isomerase P4HB/PDI, a P4HB/PDI-CD4-CXCR4-gp120 complex may form. In that complex, P4HB/PDI could reach and reduce gp120 disulfide bonds, causing major conformational changes in gp120. TXN, another PDI family member could also be involved in disulfide rearrangements in Env during fusion. These changes are transmitted to the transmembrane protein gp41 and are thought to activate its fusogenic potential by unmasking its fusion peptide.<ref>PMID:19410541</ref> Surface protein gp120 (SU) may target the virus to gut-associated lymphoid tissue (GALT) by binding host ITGA4/ITGB7 (alpha-4/beta-7 integrins), a complex that mediates T-cell migration to the GALT. Interaction between gp120 and ITGA4/ITGB7 would allow the virus to enter GALT early in the infection, infecting and killing most of GALT's resting CD4+ T-cells. This T-cell depletion is believed to be the major insult to the host immune system leading to AIDS (By similarity).<ref>PMID:19410541</ref> The surface protein gp120 is a ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on endothelial cells of liver sinusoids and lymph node sinuses. These interactions allow capture of viral particles at mucosal surfaces by these cells and subsequent transmission to permissive cells. DCs are professional antigen presenting cells, critical for host immunity by inducing specific immune responses against a broad variety of pathogens. They act as sentinels in various tissues where they take up antigen, process it, and present it to T-cells following migration to lymphoid organs. HIV subverts the migration properties of dendritic cells to gain access to CD4+ T-cells in lymph nodes. Virus transmission to permissive T-cells occurs either in trans (without DCs infection, through viral capture and transmission), or in cis (following DCs productive infection, through the usual CD4-gp120 interaction), thereby inducing a robust infection. In trans infection, bound virions remain infectious over days and it is proposed that they are not degraded, but protected in non-lysosomal acidic organelles within the DCs close to the cell membrane thus contributing to the viral infectious potential during DCs' migration from the periphery to the lymphoid tissues. On arrival at lymphoid tissues, intact virions recycle back to DCs' cell surface allowing virus transmission to CD4+ T-cells. Virion capture also seems to lead to MHC-II-restricted viral antigen presentation, and probably to the activation of HIV-specific CD4+ cells.<ref>PMID:19410541</ref> The transmembrane protein gp41 (TM) acts as a class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During fusion of viral and target intracellular membranes, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. Complete fusion occurs in host cell endosomes and is dynamin-dependent, however some lipid transfer might occur at the plasma membrane. The virus undergoes clathrin-dependent internalization long before endosomal fusion, thus minimizing the surface exposure of conserved viral epitopes during fusion and reducing the efficacy of inhibitors targeting these epitopes. Membranes fusion leads to delivery of the nucleocapsid into the cytoplasm.<ref>PMID:19410541</ref> The envelope glyprotein gp160 precursor down-modulates cell surface CD4 antigen by interacting with it in the endoplasmic reticulum and blocking its transport to the cell surface (By similarity).<ref>PMID:19410541</ref> The gp120-gp41 heterodimer seems to contribute to T-cell depletion during HIV-1 infection. The envelope glycoproteins expressed on the surface of infected cells induce apoptosis through an interaction with uninfected cells expressing the receptor (CD4) and the coreceptors CXCR4 or CCR5. This type of bystander killing may be obtained by at least three distinct mechanisms. First, the interaction between the 2 cells can induce cellular fusion followed by nuclear fusion within the syncytium. Syncytia are condemned to die from apoptosis. Second, the 2 interacting cells may not fuse entirely and simply exchange plasma membrane lipids, after a sort of hemifusion process, followed by rapid death. Third, it is possible that virus-infected cells, on the point of undergoing apoptosis, fuse with CD4-expressing cells, in which case apoptosis is rapidly transmitted from one cell to the other and thus occurs in a sort of contagious fashion.<ref>PMID:19410541</ref> The gp120-gp41 heterodimer allows rapid transcytosis of the virus through CD4 negative cells such as simple epithelial monolayers of the intestinal, rectal and endocervical epithelial barriers. Both gp120 and gp41 specifically recognize glycosphingolipids galactosyl-ceramide (GalCer) or 3' sulfo-galactosyl-ceramide (GalS) present in the lipid rafts structures of epithelial cells. Binding to these alternative receptors allows the rapid transcytosis of the virus through the epithelial cells. This transcytotic vesicle-mediated transport of virions from the apical side to the basolateral side of the epithelial cells does not involve infection of the cells themselves.<ref>PMID:19410541</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==

OCA at 23:50, 22 December 2014

OCA — Mon, 22 Dec 2014 23:50:10 GMT

←Older revision		Revision as of 23:50, 22 December 2014
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[1gzl]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GZL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1GZL FirstGlance]. <br>		<table><tr><td colspan='2'>[[1gzl]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GZL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1GZL FirstGlance]. <br>
-	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=N2P:PENTANE-1,5-DIAMINE'>N2P</scene><br>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=N2P:PENTANE-1,5-DIAMINE'>N2P</scene></td></tr>
-	<tr><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene></td></tr>	+	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene></td></tr>
-	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1dgc\|1dgc]], [[1e7t\|1e7t]], [[1env\|1env]], [[1fav\|1fav]], [[1gcl\|1gcl]], [[1gcm\|1gcm]], [[1gk6\|1gk6]], [[1ihq\|1ihq]], [[1ij0\|1ij0]], [[1ij1\|1ij1]], [[1ij2\|1ij2]], [[1ij3\|1ij3]], [[1kql\|1kql]], [[1piq\|1piq]], [[1swi\|1swi]], [[1tmz\|1tmz]], [[1ysa\|1ysa]], [[1zii\|1zii]], [[1zij\|1zij]], [[1zik\|1zik]], [[1zil\|1zil]], [[1zim\|1zim]], [[1zta\|1zta]], [[2dgc\|2dgc]], [[2zta\|2zta]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1dgc\|1dgc]], [[1e7t\|1e7t]], [[1env\|1env]], [[1fav\|1fav]], [[1gcl\|1gcl]], [[1gcm\|1gcm]], [[1gk6\|1gk6]], [[1ihq\|1ihq]], [[1ij0\|1ij0]], [[1ij1\|1ij1]], [[1ij2\|1ij2]], [[1ij3\|1ij3]], [[1kql\|1kql]], [[1piq\|1piq]], [[1swi\|1swi]], [[1tmz\|1tmz]], [[1ysa\|1ysa]], [[1zii\|1zii]], [[1zij\|1zij]], [[1zik\|1zik]], [[1zil\|1zil]], [[1zim\|1zim]], [[1zta\|1zta]], [[2dgc\|2dgc]], [[2zta\|2zta]]</td></tr>
-	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1gzl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gzl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1gzl RCSB], [http://www.ebi.ac.uk/pdbsum/1gzl PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1gzl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gzl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1gzl RCSB], [http://www.ebi.ac.uk/pdbsum/1gzl PDBsum]</span></td></tr>
-	<table>	+	</table>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 20:		Line 20:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Carr, P A.]]	+	[[Category: Carr, P A]]
-	[[Category: Cochran, A G.]]	+	[[Category: Cochran, A G]]
-	[[Category: Kim, P S.]]	+	[[Category: Kim, P S]]
-	[[Category: Malashkevich, V M.]]	+	[[Category: Malashkevich, V M]]
-	[[Category: Sia, S K.]]	+	[[Category: Sia, S K]]
	[[Category: Cross-link]]		[[Category: Cross-link]]
	[[Category: Glycoprotein]]		[[Category: Glycoprotein]]

OCA at 13:34, 28 September 2014

OCA — Sun, 28 Sep 2014 13:34:40 GMT

←Older revision		Revision as of 13:34, 28 September 2014
Line 1:		Line 1:
-	[[~~Image:~~1gzl.~~png~~\|~~left~~\|~~200px~~]]	+	==CRYSTAL STRUCTURE OF C14LINKMID/IQN17: A CROSS-LINKED INHIBITOR OF HIV-1 ENTRY BOUND TO THE GP41 HYDROPHOBIC POCKET==
		+	<StructureSection load='1gzl' size='340' side='right' caption='[[1gzl]], [[Resolution\|resolution]] 1.80Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[1gzl]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GZL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1GZL FirstGlance]. <br>
		+	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=N2P:PENTANE-1,5-DIAMINE'>N2P</scene><br>
		+	<tr><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene></td></tr>
		+	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1dgc\|1dgc]], [[1e7t\|1e7t]], [[1env\|1env]], [[1fav\|1fav]], [[1gcl\|1gcl]], [[1gcm\|1gcm]], [[1gk6\|1gk6]], [[1ihq\|1ihq]], [[1ij0\|1ij0]], [[1ij1\|1ij1]], [[1ij2\|1ij2]], [[1ij3\|1ij3]], [[1kql\|1kql]], [[1piq\|1piq]], [[1swi\|1swi]], [[1tmz\|1tmz]], [[1ysa\|1ysa]], [[1zii\|1zii]], [[1zij\|1zij]], [[1zik\|1zik]], [[1zil\|1zil]], [[1zim\|1zim]], [[1zta\|1zta]], [[2dgc\|2dgc]], [[2zta\|2zta]]</td></tr>
		+	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1gzl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gzl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1gzl RCSB], [http://www.ebi.ac.uk/pdbsum/1gzl PDBsum]</span></td></tr>
		+	<table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Peptides corresponding to the C-terminal heptad repeat of HIV-1 gp41 (C-peptides) are potent inhibitors of HIV-1 entry into cells. Their mechanism of inhibition involves binding in a helical conformation to the central coiled coil of HIV-1 gp41 in a dominant-negative manner. Short C-peptides, however, have low binding affinity for gp41 and poor inhibitory activity, which creates an obstacle to the development of small drug-like C-peptides. To improve the inhibitory potency of short C-peptides that target the hydrophobic pocket region of gp41, we use two strategies to stabilize the C-peptide helix: chemical crosslinking and substitution with unnatural helix-favoring amino acids. In this study, the short linear peptide shows no significant inhibitory activity, but a constrained peptide (C14linkmid) inhibits cell-cell fusion at micromolar potency. Structural studies confirm that the constrained peptides bind to the gp41 hydrophobic pocket. Calorimetry reveals that, of the peptides analyzed, the most potent are those that best balance the changes in binding enthalpy and entropy, and surprisingly not those with the highest helical propensity as measured by circular dichroism spectroscopy. Our study reveals the thermodynamic basis of inhibition of an HIV C-peptide, demonstrates the utility of constraining methods for a short antiviral peptide inhibitor, and has implications for the future design of constrained peptides.

-	~~{{STRUCTURE_1gzl\| PDB=1gzl \| SCENE= }}~~	+	Short constrained peptides that inhibit HIV-1 entry.,Sia SK, Carr PA, Cochran AG, Malashkevich VN, Kim PS Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14664-9. Epub 2002 Nov 4. PMID:12417739<ref>PMID:12417739</ref>

-	~~===CRYSTAL STRUCTURE OF C14LINKMID~~/~~IQN17: A CROSS-LINKED INHIBITOR OF HIV-1 ENTRY BOUND TO THE GP41 HYDROPHOBIC POCKET===~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~{{ABSTRACT_PUBMED_12417739}}~~	+	== References ==
-		+	<references/>
-	==~~About this Structure~~==	+	__TOC__
-	~~[[1gzl]] is a 4 chain structure. Full crystallographic information is available from [http:~~//~~oca.weizmann.ac.il/oca-bin/ocashort?id=1GZL OCA].~~	+	</StructureSection>
	[[Category: Carr, P A.]]		[[Category: Carr, P A.]]
	[[Category: Cochran, A G.]]		[[Category: Cochran, A G.]]