1tji - Revision history

OCA at 06:31, 23 August 2023

2023-08-23T06:31:02Z

←Older revision		Revision as of 06:31, 23 August 2023
Line 3:		Line 3:
	<StructureSection load='1tji' size='340' side='right'caption='[[1tji]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='1tji' size='340' side='right'caption='[[1tji]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[1tji]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Human ~~Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TJI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1TJI FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[1tji]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_type_1_(ZAIRE_6_ISOLATE) Human immunodeficiency virus type 1 (ZAIRE 6 ISOLATE)]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TJI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1TJI FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat" id="~~ligandDat~~">~~<scene name='pdbligand=EDO:1~~,2~~-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</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]] 2.2Å</td></tr>
-	<tr id='~~NonStdRes~~'><td class="sblockLbl"><b>[[~~Non-Standard_Residue~~\|~~NonStd Res~~:]]</b></td><td class="sblockDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=YCM:S-(2-AMINO-2-OXOETHYL)-L-CYSTEINE'>YCM</scene~~></td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=YCM:S-(2-AMINO-2-OXOETHYL)-L-CYSTEINE'>YCM</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;'>[[2f5b\|2f5b]], [[1tjg\|1tjg]], [[1tjh\|1tjh]]</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=1tji FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tji OCA], [https://pdbe.org/1tji PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1tji RCSB], [https://www.ebi.ac.uk/pdbsum/1tji PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1tji 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=1tji FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tji OCA], [https://pdbe.org/1tji PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1tji RCSB], [https://www.ebi.ac.uk/pdbsum/1tji PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1tji ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/ENV_HV1Z6 ENV_HV1Z6]] 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. 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). 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 (By similarity). 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 (By similarity). 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). 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 (By similarity). 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 (By similarity).	+	[https://www.uniprot.org/uniprot/ENV_HV1Z6 ENV_HV1Z6] 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. 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). 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 (By similarity). 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 (By similarity). 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). 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 (By similarity). 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 (By similarity).
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
Line 38:		Line 37:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Katinger, H]]	+	[[Category: Katinger H]]
-	[[Category: Kwong~~, P D~~]]	+	[[Category: Kwong PD]]
-	[[Category: Mascola~~, J R~~]]	+	[[Category: Mascola JR]]
-	[[Category: Ofek, G]]	+	[[Category: Ofek G]]
-	[[Category: Sambor, A]]	+	[[Category: Sambor A]]
-	[[Category: Tang, M]]	+	[[Category: Tang M]]
-	[[Category: Wyatt, R]]	+	[[Category: Wyatt R]]
-	~~[[Category: Antibody]]~~	+
-	~~[[Category: Gp41]]~~	+
-	~~[[Category: Hiv-1]]~~	+
-	~~[[Category: Membrane-proximal]]~~	+
-	~~[[Category: Neutralizing]]~~	+
-	~~[[Category: Viral protein-immune system complex~~]]	+

OCA at 09:28, 29 September 2021

2021-09-29T09:28:37Z

←Older revision		Revision as of 09:28, 29 September 2021
Line 3:		Line 3:
	<StructureSection load='1tji' size='340' side='right'caption='[[1tji]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='1tji' size='340' side='right'caption='[[1tji]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[1tji]] is a 3 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TJI OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=1TJI FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[1tji]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TJI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1TJI FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene></td></tr>
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=YCM:S-(2-AMINO-2-OXOETHYL)-L-CYSTEINE'>YCM</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=YCM:S-(2-AMINO-2-OXOETHYL)-L-CYSTEINE'>YCM</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2f5b\|2f5b]], [[1tjg\|1tjg]], [[1tjh\|1tjh]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2f5b\|2f5b]], [[1tjg\|1tjg]], [[1tjh\|1tjh]]</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=1tji FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tji OCA], [~~http~~://pdbe.org/1tji PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=1tji RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/1tji PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=1tji 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=1tji FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tji OCA], [https://pdbe.org/1tji PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1tji RCSB], [https://www.ebi.ac.uk/pdbsum/1tji PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1tji ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/ENV_HV1Z6 ENV_HV1Z6]] 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. 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). 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 (By similarity). 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 (By similarity). 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). 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 (By similarity). 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 (By similarity).	+	[[https://www.uniprot.org/uniprot/ENV_HV1Z6 ENV_HV1Z6]] 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. 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). 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 (By similarity). 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 (By similarity). 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). 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 (By similarity). 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 (By similarity).
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
Line 33:		Line 33:
	==See Also==		==See Also==
	*[[Antibody 3D structures\|Antibody 3D structures]]		*[[Antibody 3D structures\|Antibody 3D structures]]
		+	*[[3D structures of human antibody\|3D structures of human antibody]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 14:13, 25 December 2019

2019-12-25T14:13:43Z

←Older revision		Revision as of 14:13, 25 December 2019
Line 1:		Line 1:

	==Crystal Structure of the broadly neutralizing anti-HIV-1 antibody 2F5 in complex with a gp41 17mer epitope==		==Crystal Structure of the broadly neutralizing anti-HIV-1 antibody 2F5 in complex with a gp41 17mer epitope==
-	<StructureSection load='1tji' size='340' side='right' caption='[[1tji]], [[Resolution\|resolution]] 2.20Å' scene=''>	+	<StructureSection load='1tji' size='340' side='right'caption='[[1tji]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[1tji]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TJI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1TJI FirstGlance]. <br>		<table><tr><td colspan='2'>[[1tji]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TJI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1TJI FirstGlance]. <br>
Line 38:		Line 38:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Katinger, H]]		[[Category: Katinger, H]]
	[[Category: Kwong, P D]]		[[Category: Kwong, P D]]

OCA at 09:02, 21 March 2018

2018-03-21T09:02:10Z

←Older revision		Revision as of 09:02, 21 March 2018
Line 1:		Line 1:
		+
	==Crystal Structure of the broadly neutralizing anti-HIV-1 antibody 2F5 in complex with a gp41 17mer epitope==		==Crystal Structure of the broadly neutralizing anti-HIV-1 antibody 2F5 in complex with a gp41 17mer epitope==
	<StructureSection load='1tji' size='340' side='right' caption='[[1tji]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='1tji' size='340' side='right' caption='[[1tji]], [[Resolution\|resolution]] 2.20Å' 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=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=YCM:S-(2-AMINO-2-OXOETHYL)-L-CYSTEINE'>YCM</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=YCM:S-(2-AMINO-2-OXOETHYL)-L-CYSTEINE'>YCM</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2f5b\|2f5b]], [[1tjg\|1tjg]], [[1tjh\|1tjh]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2f5b\|2f5b]], [[1tjg\|1tjg]], [[1tjh\|1tjh]]</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=1tji FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tji OCA], [http://pdbe.org/1tji PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1tji RCSB], [http://www.ebi.ac.uk/pdbsum/1tji 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=1tji FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tji OCA], [http://pdbe.org/1tji PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1tji RCSB], [http://www.ebi.ac.uk/pdbsum/1tji PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1tji ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 14:		Line 15:
	Check<jmol>		Check<jmol>
	<jmolCheckbox>		<jmolCheckbox>
-	<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/tj/1tji_consurf.spt"</scriptWhenChecked>	+	<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/tj/1tji_consurf.spt"</scriptWhenChecked>
	<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>		<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
	<text>to colour the structure by Evolutionary Conservation</text>		<text>to colour the structure by Evolutionary Conservation</text>
	</jmolCheckbox>		</jmolCheckbox>
-	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/~~chain_selection~~.php?pdb_ID=~~2ata~~ ConSurf].	+	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1tji ConSurf].
	<div style="clear:both"></div>		<div style="clear:both"></div>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
Line 31:		Line 32:

	==See Also==		==See Also==
-	*[[Antibody\|Antibody]]	+	*[[Antibody 3D structures\|Antibody 3D structures]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 08:51, 11 September 2015

2015-09-11T08:51:18Z

←Older revision		Revision as of 08:51, 11 September 2015
Line 2:		Line 2:
	<StructureSection load='1tji' size='340' side='right' caption='[[1tji]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='1tji' size='340' side='right' caption='[[1tji]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[1tji]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TJI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1TJI FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[1tji]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TJI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1TJI FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene></td></tr>
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=YCM:S-(2-AMINO-2-OXOETHYL)-L-CYSTEINE'>YCM</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=YCM:S-(2-AMINO-2-OXOETHYL)-L-CYSTEINE'>YCM</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2f5b\|2f5b]], [[1tjg\|1tjg]], [[1tjh\|1tjh]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2f5b\|2f5b]], [[1tjg\|1tjg]], [[1tjh\|1tjh]]</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=1tji FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tji OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1tji RCSB], [http://www.ebi.ac.uk/pdbsum/1tji 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=1tji FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tji OCA], [http://pdbe.org/1tji PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1tji RCSB], [http://www.ebi.ac.uk/pdbsum/1tji PDBsum]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 28:		Line 28:
	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 1tji" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 35:		Line 36:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Katinger, H]]		[[Category: Katinger, H]]
	[[Category: Kwong, P D]]		[[Category: Kwong, P D]]

OCA at 14:06, 25 December 2014

2014-12-25T14:06:11Z

←Older revision		Revision as of 14:06, 25 December 2014
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[1tji]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TJI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1TJI FirstGlance]. <br>		<table><tr><td colspan='2'>[[1tji]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TJI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1TJI FirstGlance]. <br>
-	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene><br>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene></td></tr>
-	<tr><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=YCM:S-(2-AMINO-2-OXOETHYL)-L-CYSTEINE'>YCM</scene></td></tr>	+	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=YCM:S-(2-AMINO-2-OXOETHYL)-L-CYSTEINE'>YCM</scene></td></tr>
-	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2f5b\|2f5b]], [[1tjg\|1tjg]], [[1tjh\|1tjh]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2f5b\|2f5b]], [[1tjg\|1tjg]], [[1tjh\|1tjh]]</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=1tji FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tji OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1tji RCSB], [http://www.ebi.ac.uk/pdbsum/1tji 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=1tji FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tji OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1tji RCSB], [http://www.ebi.ac.uk/pdbsum/1tji PDBsum]</span></td></tr>
-	<table>	+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/ENV_HV1Z6 ENV_HV1Z6]] 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. 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). 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 (By similarity). 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 (By similarity). 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). 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 (By similarity). 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 (By similarity).
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
Line 34:		Line 36:
	</StructureSection>		</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
-	[[Category: Katinger, H.]]	+	[[Category: Katinger, H]]
-	[[Category: Kwong, P D.]]	+	[[Category: Kwong, P D]]
-	[[Category: Mascola, J R.]]	+	[[Category: Mascola, J R]]
-	[[Category: Ofek, G.]]	+	[[Category: Ofek, G]]
-	[[Category: Sambor, A.]]	+	[[Category: Sambor, A]]
-	[[Category: Tang, M.]]	+	[[Category: Tang, M]]
-	[[Category: Wyatt, R~~.]]~~	+	[[Category: Wyatt, R]]
-	~~[[Category: 2f5~~]]	+
	[[Category: Antibody]]		[[Category: Antibody]]
	[[Category: Gp41]]		[[Category: Gp41]]

OCA at 21:10, 29 September 2014

2014-09-29T21:10:03Z

←Older revision		Revision as of 21:10, 29 September 2014
Line 1:		Line 1:
-	[[~~Image:~~1tji.~~png~~\|~~left~~\|200px]]	+	==Crystal Structure of the broadly neutralizing anti-HIV-1 antibody 2F5 in complex with a gp41 17mer epitope==
		+	<StructureSection load='1tji' size='340' side='right' caption='[[1tji]], [[Resolution\|resolution]] 2.20Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[1tji]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TJI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1TJI FirstGlance]. <br>
		+	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene><br>
		+	<tr><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=YCM:S-(2-AMINO-2-OXOETHYL)-L-CYSTEINE'>YCM</scene></td></tr>
		+	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2f5b\|2f5b]], [[1tjg\|1tjg]], [[1tjh\|1tjh]]</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=1tji FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tji OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1tji RCSB], [http://www.ebi.ac.uk/pdbsum/1tji PDBsum]</span></td></tr>
		+	<table>
		+	== Evolutionary Conservation ==
		+	[[Image:Consurf_key_small.gif\|200px\|right]]
		+	Check<jmol>
		+	<jmolCheckbox>
		+	<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/tj/1tji_consurf.spt"</scriptWhenChecked>
		+	<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
		+	<text>to colour the structure by Evolutionary Conservation</text>
		+	</jmolCheckbox>
		+	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
		+	<div style="clear:both"></div>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The membrane-proximal region of the ectodomain of the gp41 envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) is the target of three of the five broadly neutralizing anti-HIV-1 antibodies thus far isolated. We have determined crystal structures of the antigen-binding fragment for one of these antibodies, 2F5, in complex with 7-mer, 11-mer, and 17-mer peptides of the gp41 membrane-proximal region, at 2.0-, 2.1-, and 2.2-A resolutions, respectively. The structures reveal an extended gp41 conformation, which stretches over 30 A in length. Contacts are made with five complementarity-determining regions of the antibody as well as with nonpolymorphic regions. Only one exclusive charged face of the gp41 epitope is bound by 2F5, while the nonbound face, which is hydrophobic, may be hidden due to occlusion by other portions of the ectodomain. The structures reveal that the 2F5 antibody is uniquely built to bind to an epitope that is proximal to a membrane surface and in a manner mostly unaffected by large-scale steric hindrance. Biochemical studies with proteoliposomes confirm the importance of lipid membrane and hydrophobic context in the binding of 2F5 as well as in the binding of 4E10, another broadly neutralizing antibody that recognizes the membrane-proximal region of gp41. Based on these structural and biochemical results, immunization strategies for eliciting 2F5- and 4E10-like broadly neutralizing anti-HIV-1 antibodies are proposed.

-	~~{{STRUCTURE_1tji\| PDB=1tji \| SCENE= }}~~	+	Structure and mechanistic analysis of the anti-human immunodeficiency virus type 1 antibody 2F5 in complex with its gp41 epitope.,Ofek G, Tang M, Sambor A, Katinger H, Mascola JR, Wyatt R, Kwong PD J Virol. 2004 Oct;78(19):10724-37. PMID:15367639<ref>PMID:15367639</ref>

-	~~===Crystal Structure~~ of the ~~broadly neutralizing anti-HIV-1 antibody 2F5 in complex with a gp41 17mer epitope===~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>

-	~~{{ABSTRACT_PUBMED_15367639}}~~	+	==See Also==
-		+	*[[Antibody\|Antibody]]
-	==~~About this Structure~~==	+	== References ==
-	[[~~1tji~~]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TJI OCA].	+	<references/>
-		+	__TOC__
-	==~~Reference~~==	+	</StructureSection>
-	<~~ref group="xtra">PMID:015367639<~~/~~ref~~><~~references group="xtra"~~/>	+
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Katinger, H.]]		[[Category: Katinger, H.]]

OCA: Protected "1tji" [edit=sysop:move=sysop]

2013-01-05T12:13:57Z

Protected "1tji" [edit=sysop:move=sysop]

←Older revision

Revision as of 12:13, 5 January 2013

OCA at 12:13, 5 January 2013

2013-01-05T12:13:54Z

←Older revision		Revision as of 12:13, 5 January 2013
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-	{{Seed}}
	[[Image:1tji.png\|left\|200px]]		[[Image:1tji.png\|left\|200px]]

-	<!--
-	The line below this paragraph, containing "STRUCTURE_1tji", creates the "Structure Box" on the page.
-	You may change the PDB parameter (which sets the PDB file loaded into the applet)
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	{{STRUCTURE_1tji\| PDB=1tji \| SCENE= }}		{{STRUCTURE_1tji\| PDB=1tji \| SCENE= }}

	===Crystal Structure of the broadly neutralizing anti-HIV-1 antibody 2F5 in complex with a gp41 17mer epitope===		===Crystal Structure of the broadly neutralizing anti-HIV-1 antibody 2F5 in complex with a gp41 17mer epitope===

-
-	<!--
-	The line below this paragraph, {{ABSTRACT_PUBMED_15367639}}, adds the Publication Abstract to the page
-	(as it appears on PubMed at http://www.pubmed.gov), where 15367639 is the PubMed ID number.
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	{{ABSTRACT_PUBMED_15367639}}		{{ABSTRACT_PUBMED_15367639}}

	==About this Structure==		==About this Structure==
-	~~1TJI~~ is a 3 ~~chains~~ structure ~~of sequences~~ from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TJI OCA].	+	[[1tji]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TJI OCA].

	==Reference==		==Reference==
-	<ref group="xtra">PMID:~~15367639~~</ref><references group="xtra"/>	+	<ref group="xtra">PMID:015367639</ref><references group="xtra"/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Katinger, H.]]		[[Category: Katinger, H.]]
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	[[Category: Membrane-proximal]]		[[Category: Membrane-proximal]]
	[[Category: Neutralizing]]		[[Category: Neutralizing]]
-		+	[[Category: Viral protein-immune system complex]]
-	~~''Page seeded by~~ [~~http~~:~~//oca.weizmann.ac.il/oca OCA~~ ] ~~on Tue Feb 17 18:14:14 2009''~~	+

OCA at 16:14, 17 February 2009

2009-02-17T16:14:15Z

←Older revision		Revision as of 16:14, 17 February 2009
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	==About this Structure==		==About this Structure==
-	1TJI is a ~~[[Single protein]]~~ structure of ~~sequence~~ from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TJI OCA].	+	1TJI is a 3 chains structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TJI OCA].

	==Reference==		==Reference==
-	Structure and mechanistic analysis of the anti-human immunodeficiency virus type 1 antibody 2F5 in complex with its gp41 epitope., Ofek G, Tang M, Sambor A, Katinger H, Mascola JR, Wyatt R, Kwong PD, J Virol. 2004 Oct;78(19):10724-37. PMID:~~[http:~~//~~www.ncbi.nlm.nih.gov/pubmed/15367639 15367639]~~	+	<ref group="xtra">PMID:15367639</ref><references group="xtra"/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
-	[[Category: Single protein]]
	[[Category: Katinger, H.]]		[[Category: Katinger, H.]]
	[[Category: Kwong, P D.]]		[[Category: Kwong, P D.]]
Line 40:		Line 39:
	[[Category: Neutralizing]]		[[Category: Neutralizing]]

-	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue ~~Jul 29 02~~:01:~~43 2008~~''	+	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Feb 17 18:14:14 2009''