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==== | ==Asymmetric model of CD4-bound B41 HIV-1 Env SOSIP in complex with small molecule GO52== | ||
<StructureSection load='6x5c' size='340' side='right'caption='[[6x5c]]' scene=''> | <StructureSection load='6x5c' size='340' side='right'caption='[[6x5c]], [[Resolution|resolution]] 4.04Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6x5c]] is a 9 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=6X5C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6X5C FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.04Å</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>, <scene name='pdbligand=UOV:~{N}-[4-(4-methylphenyl)phenyl]-1-oxa-7-azaspiro[3.5]nonane-7-carboxamide'>UOV</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=6x5c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6x5c OCA], [https://pdbe.org/6x5c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6x5c RCSB], [https://www.ebi.ac.uk/pdbsum/6x5c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6x5c ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/B3UES2_9HIV1 B3UES2_9HIV1] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Disruption of viral fusion represents a viable, albeit under-explored, target for HIV therapeutics. Here, while studying the receptor-bound envelope glycoprotein conformation by cryoelectron microscopy (cryo-EM), we identify a pocket near the base of the trimer containing a bound detergent molecule and perform in silico drug screening by using a library of drug-like and commercially available molecules. After down-selection, we solve cryo-EM structures that validate the binding of two small molecule hits in very similar manners to the predicted binding poses, including interactions with aromatic residues within the fusion peptide. One of the molecules demonstrates low micromolar inhibition of the autologous virus by using a very rare phenylalanine in the fusion peptide and stabilizing the surrounding region. This work demonstrates that small molecules can target the fusion process, providing an additional target for anti-HIV therapeutics, and highlights the need to explore how fusion peptide sequence variations affect receptor-mediated conformational states across diverse HIV strains. | |||
A Strain-Specific Inhibitor of Receptor-Bound HIV-1 Targets a Pocket near the Fusion Peptide.,Ozorowski G, Torres JL, Santos-Martins D, Forli S, Ward AB Cell Rep. 2020 Nov 24;33(8):108428. doi: 10.1016/j.celrep.2020.108428. PMID:33238117<ref>PMID:33238117</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6x5c" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Gp41 3D Structures|Gp41 3D Structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Human immunodeficiency virus 1]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Ozorowski G]] | ||
[[Category: Torres JL]] | |||
[[Category: Ward AB]] | |||
Latest revision as of 16:17, 6 November 2024
Asymmetric model of CD4-bound B41 HIV-1 Env SOSIP in complex with small molecule GO52Asymmetric model of CD4-bound B41 HIV-1 Env SOSIP in complex with small molecule GO52
Structural highlights
FunctionPublication Abstract from PubMedDisruption of viral fusion represents a viable, albeit under-explored, target for HIV therapeutics. Here, while studying the receptor-bound envelope glycoprotein conformation by cryoelectron microscopy (cryo-EM), we identify a pocket near the base of the trimer containing a bound detergent molecule and perform in silico drug screening by using a library of drug-like and commercially available molecules. After down-selection, we solve cryo-EM structures that validate the binding of two small molecule hits in very similar manners to the predicted binding poses, including interactions with aromatic residues within the fusion peptide. One of the molecules demonstrates low micromolar inhibition of the autologous virus by using a very rare phenylalanine in the fusion peptide and stabilizing the surrounding region. This work demonstrates that small molecules can target the fusion process, providing an additional target for anti-HIV therapeutics, and highlights the need to explore how fusion peptide sequence variations affect receptor-mediated conformational states across diverse HIV strains. A Strain-Specific Inhibitor of Receptor-Bound HIV-1 Targets a Pocket near the Fusion Peptide.,Ozorowski G, Torres JL, Santos-Martins D, Forli S, Ward AB Cell Rep. 2020 Nov 24;33(8):108428. doi: 10.1016/j.celrep.2020.108428. PMID:33238117[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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