View source for 9aug


==Cryo-EM structure of CH848.d949.10.17.GS-DH270.UCA3.G57R==
<StructureSection load='9aug' size='340' side='right'caption='[[9aug]], [[Resolution|resolution]] 3.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9aug]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9AUG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9AUG FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9aug FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9aug OCA], [https://pdbe.org/9aug PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9aug RCSB], [https://www.ebi.ac.uk/pdbsum/9aug PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9aug ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q2N0S6_HV1 Q2N0S6_HV1] 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]
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== Publication Abstract from PubMed ==
Elicitation of HIV broadly neutralizing antibodies (bnAbs) by vaccination first requires the activation of diverse precursors, followed by successive boosts that guide these responses to enhanced breadth through the acquisition of somatic mutations. Because HIV bnAbs contain mutations in their B cell receptors (BCRs) that are rarely generated during conventional B cell maturation, HIV vaccine immunogens must robustly engage and expand B cells with BCRs that contain these improbable mutations. Here, we engineered an immunogen that activates diverse precursors of an HIV V3-glycan bnAb and promotes their acquisition of a functionally critical improbable mutation. This immunogen was validated biochemically, structurally, and in three different humanized immunoglobulin mouse models that were designed to test HIV immunogens. These results provide a blueprint for rationally designing priming immunogens that explicitly target the elicitation of antibodies with functional yet improbable mutations.

An engineered immunogen activates diverse HIV broadly neutralizing antibody precursors and promotes acquisition of improbable mutations.,Swanson OM, Zhang QE, Van Itallie E, Tian M, Brown AR, Harris C, Kapingidza AB, Rhodes B, Smith LM, Venkatayogi S, Cronin K, Frazier M, Parks R, Bar M, Jiang C, Martin Beem JS, Cheng HL, Davis J, McGovern K, Newman A, Edwards RJ, Cain D, Alam SM, Wiehe K, Saunders KO, Acharya P, Alt F, Haynes BF, Azoitei ML Sci Transl Med. 2025 Jan 8;17(780):eadr2218. doi: 10.1126/scitranslmed.adr2218. , Epub 2025 Jan 8. PMID:39772772<ref>PMID:39772772</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Human immunodeficiency virus 1]]
[[Category: Large Structures]]
[[Category: Acharya P]]
[[Category: Zhang QE]]