5hm1 - Revision history

OCA at 10:46, 16 August 2023

2023-08-16T10:46:42Z

←Older revision		Revision as of 10:46, 16 August 2023
Line 3:		Line 3:
	<StructureSection load='5hm1' size='340' side='right'caption='[[5hm1]], [[Resolution\|resolution]] 2.96Å' scene=''>		<StructureSection load='5hm1' size='340' side='right'caption='[[5hm1]], [[Resolution\|resolution]] 2.96Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5hm1]] is a 6 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Camelus_glama Camelus~~ glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HM1 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5HM1 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5hm1]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/HIV-1_M:B_HXB2R HIV-1 M:B_HXB2R] and [https://en.wikipedia.org/wiki/Lama_glama Lama glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HM1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HM1 FirstGlance]. <br>
-	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=5hm1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hm1 OCA], [~~http~~://pdbe.org/5hm1 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5hm1 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5hm1 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5hm1 ProSAT]</span></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]] 2.962Å</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=5hm1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hm1 OCA], [https://pdbe.org/5hm1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hm1 RCSB], [https://www.ebi.ac.uk/pdbsum/5hm1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hm1 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>

	==See Also==		==See Also==
	*[[Antibody 3D structures\|Antibody 3D structures]]		*[[Antibody 3D structures\|Antibody 3D structures]]
	*[[Gp41 3D Structures\|Gp41 3D Structures]]		*[[Gp41 3D Structures\|Gp41 3D Structures]]
		+	*[[3D structures of non-human antibody\|3D structures of non-human antibody]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Camelus~~ glama]]	+	[[Category: HIV-1 M:B_HXB2R]]
		+	[[Category: Lama glama]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Caillat, C]]	+	[[Category: Caillat C]]
-	[[Category: Haffke, M]]	+	[[Category: Haffke M]]
-	[[Category: Hock, M]]	+	[[Category: Hock M]]
-	[[Category: Weissenhorn, W]]	+	[[Category: Weissenhorn W]]
-	~~[[Category: Antibody]]~~	+
-	~~[[Category: Gp120]]~~	+
-	~~[[Category: Gp41]]~~	+
-	~~[[Category: Hiv]]~~	+
-	~~[[Category: Immune system~~]]	+

OCA at 08:22, 27 May 2020

2020-05-27T08:22:34Z

←Older revision		Revision as of 08:22, 27 May 2020
Line 1:		Line 1:

	==Llama VHH 2E7 in complex with gp41==		==Llama VHH 2E7 in complex with gp41==
-	<StructureSection load='5hm1' size='340' side='right' caption='[[5hm1]], [[Resolution\|resolution]] 2.96Å' scene=''>	+	<StructureSection load='5hm1' size='340' side='right'caption='[[5hm1]], [[Resolution\|resolution]] 2.96Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5hm1]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HM1 OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5HM1 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5hm1]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Camelus_glama Camelus glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HM1 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5HM1 FirstGlance]. <br>
-	</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=5hm1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hm1 OCA], [http://pdbe.org/5hm1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hm1 RCSB], [http://www.ebi.ac.uk/pdbsum/5hm1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5hm1 ProSAT]</span></td></tr>	+	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5hm1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hm1 OCA], [http://pdbe.org/5hm1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hm1 RCSB], [http://www.ebi.ac.uk/pdbsum/5hm1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5hm1 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 10:		Line 10:

	==See Also==		==See Also==
-	*[[3D structures ~~of antibody~~\|3D structures ~~of antibody~~]]	+	*[[Antibody 3D structures\|Antibody 3D structures]]
		+	*[[Gp41 3D Structures\|Gp41 3D Structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Camelus glama]]
		+	[[Category: Large Structures]]
	[[Category: Caillat, C]]		[[Category: Caillat, C]]
	[[Category: Haffke, M]]		[[Category: Haffke, M]]

OCA at 16:54, 9 March 2017

2017-03-09T16:54:58Z

←Older revision		Revision as of 16:54, 9 March 2017
Line 8:		Line 8:
	== 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>		[[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>
		+
		+	==See Also==
		+	*[[3D structures of antibody\|3D structures of antibody]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 23:41, 25 January 2017

2017-01-25T23:41:51Z

←Older revision		Revision as of 23:41, 25 January 2017
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5hm1 ~~is ON HOLD until Paper Publication~~	+	==Llama VHH 2E7 in complex with gp41==
-		+	<StructureSection load='5hm1' size='340' side='right' caption='[[5hm1]], [[Resolution\|resolution]] 2.96Å' scene=''>
-	~~Authors~~: ~~Hock~~, M., ~~Caillat~~, C., ~~Haffke, M~~., ~~Weissenhorn, W~~.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[5hm1]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HM1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HM1 FirstGlance]. <br>
-	~~Description: Llama VHH 2E7 in complex with gp41~~	+	</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=5hm1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hm1 OCA], [http://pdbe.org/5hm1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hm1 RCSB], [http://www.ebi.ac.uk/pdbsum/5hm1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5hm1 ProSAT]</span></td></tr>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	</table>
-	[[Category: ~~Weissenhorn~~, W]]	+	== 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>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Caillat, C]]
	[[Category: Haffke, M]]		[[Category: Haffke, M]]
	[[Category: Hock, M]]		[[Category: Hock, M]]
-	[[Category: ~~Caillat~~, C]]	+	[[Category: Weissenhorn, W]]
		+	[[Category: Antibody]]
		+	[[Category: Gp120]]
		+	[[Category: Gp41]]
		+	[[Category: Hiv]]
		+	[[Category: Immune system]]

OCA at 09:55, 18 January 2017

2017-01-18T09:55:45Z

←Older revision		Revision as of 09:55, 18 January 2017
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	Authors: Hock, M., Caillat, C., Haffke, M., Weissenhorn, W.		Authors: Hock, M., Caillat, C., Haffke, M., Weissenhorn, W.

-	Description: ~~Superpotent bi-specific llama~~ VHH ~~antibodies neutralize HIV via~~ gp41 ~~and gp120 epitopes. Epitope characterization on G120 and gp41 used to design bi-specific superpotent broadly HIV neutralizing VHH~~	+	Description: Llama VHH 2E7 in complex with gp41
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
	[[Category: Weissenhorn, W]]		[[Category: Weissenhorn, W]]

OCA at 21:53, 12 July 2016

2016-07-12T21:53:19Z

←Older revision		Revision as of 21:53, 12 July 2016
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5hm1 is ON HOLD	+	The entry 5hm1 is ON HOLD until Paper Publication

-	Authors: ~~Strokappe, N.M.,~~ Hock, M~~., Rutten, L., McCoy, L.E., Back, J.W~~., Caillat, C., Haffke, M~~., Weiss, R.A., Chen, L., Kwong, P~~., Weissenhorn, W~~., Verrips, T~~.	+	Authors: Hock, M., Caillat, C., Haffke, M., Weissenhorn, W.

	Description: Superpotent bi-specific llama VHH antibodies neutralize HIV via gp41 and gp120 epitopes. Epitope characterization on G120 and gp41 used to design bi-specific superpotent broadly HIV neutralizing VHH		Description: Superpotent bi-specific llama VHH antibodies neutralize HIV via gp41 and gp120 epitopes. Epitope characterization on G120 and gp41 used to design bi-specific superpotent broadly HIV neutralizing VHH
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Verrips, T]]
-	[[Category: Kwong, P]]
	[[Category: Weissenhorn, W]]		[[Category: Weissenhorn, W]]
	[[Category: Haffke, M]]		[[Category: Haffke, M]]
-	[[Category: Back, J.W]]
-	[[Category: Weiss, R.A]]
-	[[Category: Strokappe, N.M]]
-	[[Category: Rutten, L]]
-	[[Category: Chen, L]]
	[[Category: Hock, M]]		[[Category: Hock, M]]
	[[Category: Caillat, C]]		[[Category: Caillat, C]]
-	[[Category: Mccoy, L.E]]

OCA: Protected "5hm1" [edit=sysop:move=sysop]

2016-01-28T00:51:25Z

Protected "5hm1" [edit=sysop:move=sysop]

←Older revision

Revision as of 00:51, 28 January 2016

OCA: New page: '''Unreleased structure''' The entry 5hm1 is ON HOLD Authors: Strokappe, N.M., Hock, M., Rutten, L., McCoy, L.E., Back, J.W., Caillat, C., Haffke, M., Weiss, R.A., Chen, L., Kwong, P., ...

2016-01-28T00:51:23Z

New page: '''Unreleased structure''' The entry 5hm1 is ON HOLD Authors: Strokappe, N.M., Hock, M., Rutten, L., McCoy, L.E., Back, J.W., Caillat, C., Haffke, M., Weiss, R.A., Chen, L., Kwong, P., ...

New page

'''Unreleased structure'''

The entry 5hm1 is ON HOLD

Authors: Strokappe, N.M., Hock, M., Rutten, L., McCoy, L.E., Back, J.W., Caillat, C., Haffke, M., Weiss, R.A., Chen, L., Kwong, P., Weissenhorn, W., Verrips, T.

Description: Superpotent bi-specific llama VHH antibodies neutralize HIV via gp41 and gp120 epitopes. Epitope characterization on G120 and gp41 used to design bi-specific superpotent broadly HIV neutralizing VHH
[[Category: Unreleased Structures]]
[[Category: Verrips, T]]
[[Category: Kwong, P]]
[[Category: Weissenhorn, W]]
[[Category: Haffke, M]]
[[Category: Back, J.W]]
[[Category: Weiss, R.A]]
[[Category: Strokappe, N.M]]
[[Category: Rutten, L]]
[[Category: Chen, L]]
[[Category: Hock, M]]
[[Category: Caillat, C]]
[[Category: Mccoy, L.E]]