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| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8sxj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8sxj OCA], [https://pdbe.org/8sxj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8sxj RCSB], [https://www.ebi.ac.uk/pdbsum/8sxj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8sxj 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=8sxj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8sxj OCA], [https://pdbe.org/8sxj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8sxj RCSB], [https://www.ebi.ac.uk/pdbsum/8sxj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8sxj ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Function == | + | <div style="background-color:#fffaf0;"> |
| - | [https://www.uniprot.org/uniprot/M4M3Q1_9HIV1 M4M3Q1_9HIV1] Envelope glycoprotein gp160: Oligomerizes in the host endoplasmic reticulum into predominantly trimers. In a second time, gp160 transits in the host Golgi, where glycosylation is completed. The precursor is then proteolytically cleaved in the trans-Golgi and thereby activated by cellular furin or furin-like proteases to produce gp120 and gp41.[HAMAP-Rule:MF_04083] Surface protein gp120: 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. Acts as 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. 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.[HAMAP-Rule:MF_04083] Transmembrane protein gp41: 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.[HAMAP-Rule:MF_04083]
| + | == Publication Abstract from PubMed == |
| | + | The HIV-1 Envelope (Env) glycoprotein facilitates host cell fusion through a complex series of receptor-induced structural changes. Although remarkable progress has been made in understanding the structures of various Env conformations, microsecond timescale dynamics have not been studied experimentally. Here, we used time-resolved, temperature-jump small-angle x-ray scattering to monitor structural rearrangements in an HIV-1 Env SOSIP ectodomain construct with microsecond precision. In two distinct Env variants, we detected a transition that correlated with known Env structure rearrangements with a time constant in the hundreds of microseconds range. A previously unknown structural transition was also observed, which occurred with a time constant below 10 mus, and involved an order-to-disorder transition in the trimer apex. Using this information, we engineered an Env SOSIP construct that locks the trimer in the prefusion closed state by connecting adjacent protomers via disulfides. Our findings show that the microsecond timescale structural dynamics play an essential role in controlling the Env conformation with impacts on vaccine design. |
| | + | |
| | + | Microsecond dynamics control the HIV-1 Envelope conformation.,Bennett AL, Edwards R, Kosheleva I, Saunders C, Bililign Y, Williams A, Bubphamala P, Manosouri K, Anasti K, Saunders KO, Alam SM, Haynes BF, Acharya P, Henderson R Sci Adv. 2024 Feb 2;10(5):eadj0396. doi: 10.1126/sciadv.adj0396. Epub 2024 Feb 2. PMID:38306419<ref>PMID:38306419</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 8sxj" style="background-color:#fffaf0;"></div> |
| | + | == References == |
| | + | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| Structural highlights
Publication Abstract from PubMed
The HIV-1 Envelope (Env) glycoprotein facilitates host cell fusion through a complex series of receptor-induced structural changes. Although remarkable progress has been made in understanding the structures of various Env conformations, microsecond timescale dynamics have not been studied experimentally. Here, we used time-resolved, temperature-jump small-angle x-ray scattering to monitor structural rearrangements in an HIV-1 Env SOSIP ectodomain construct with microsecond precision. In two distinct Env variants, we detected a transition that correlated with known Env structure rearrangements with a time constant in the hundreds of microseconds range. A previously unknown structural transition was also observed, which occurred with a time constant below 10 mus, and involved an order-to-disorder transition in the trimer apex. Using this information, we engineered an Env SOSIP construct that locks the trimer in the prefusion closed state by connecting adjacent protomers via disulfides. Our findings show that the microsecond timescale structural dynamics play an essential role in controlling the Env conformation with impacts on vaccine design.
Microsecond dynamics control the HIV-1 Envelope conformation.,Bennett AL, Edwards R, Kosheleva I, Saunders C, Bililign Y, Williams A, Bubphamala P, Manosouri K, Anasti K, Saunders KO, Alam SM, Haynes BF, Acharya P, Henderson R Sci Adv. 2024 Feb 2;10(5):eadj0396. doi: 10.1126/sciadv.adj0396. Epub 2024 Feb 2. PMID:38306419[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bennett AL, Edwards R, Kosheleva I, Saunders C, Bililign Y, Williams A, Bubphamala P, Manosouri K, Anasti K, Saunders KO, Alam SM, Haynes BF, Acharya P, Henderson R. Microsecond dynamics control the HIV-1 Envelope conformation. Sci Adv. 2024 Feb 2;10(5):eadj0396. PMID:38306419 doi:10.1126/sciadv.adj0396
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