7m9f
From Proteopedia
(Difference between revisions)
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==Structure of the wild-type native full-length HIV-1 capsid protein in complex with ZW-1261== | ==Structure of the wild-type native full-length HIV-1 capsid protein in complex with ZW-1261== | ||
| - | <StructureSection load='7m9f' size='340' side='right'caption='[[7m9f]]' scene=''> | + | <StructureSection load='7m9f' size='340' side='right'caption='[[7m9f]], [[Resolution|resolution]] 2.70Å' 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=7M9F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7M9F FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7m9f]] is a 1 chain structure with sequence from [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=7M9F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7M9F FirstGlance]. <br> |
| - | </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=7m9f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7m9f OCA], [https://pdbe.org/7m9f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7m9f RCSB], [https://www.ebi.ac.uk/pdbsum/7m9f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7m9f 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]] 2.7Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=YTG:N-(4-chlorophenyl)-Nalpha-[(5-hydroxy-1H-indol-3-yl)acetyl]-N-methyl-L-phenylalaninamide'>YTG</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=7m9f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7m9f OCA], [https://pdbe.org/7m9f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7m9f RCSB], [https://www.ebi.ac.uk/pdbsum/7m9f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7m9f ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/GAG_HV1N5 GAG_HV1N5] Matrix protein p17 targets Gag and Gag-Pol polyproteins to the plasma membrane via a multipartite membrane binding signal, that includes its myristoylated N-terminus. Also mediates nuclear localization of the preintegration complex. Implicated in the release from host cell mediated by Vpu. Capsid protein p24 forms the conical core of the virus that encapsulates the genomic RNA-nucleocapsid complex. Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced (genomic) RNA. Binds these RNAs through its zinc fingers. p6-gag plays a role in budding of the assembled particle by interacting with the host class E VPS proteins TSG101 and PDCD6IP/AIP1 (By similarity). | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | While drug resistance mutations can often be attributed to the loss of direct or solvent-mediated protein-ligand interactions in the drug-mutant complex, in this study we show that a resistance mutation for the picomolar HIV-1 capsid (CA)-targeting antiviral (GS-6207) is mainly due to the free energy cost of the drug-induced protein side chain reorganization in the mutant protein. Among several mutations, M66I causes the most suppression of the GS-6207 antiviral activity (up to ~84,000-fold), and only 83- and 68-fold reductions for PF74 and ZW-1261, respectively. To understand the molecular basis of this drug resistance, we conducted molecular dynamics free energy simulations to study the structures, energetics, and conformational free energy landscapes involved in the inhibitors binding at the interface of two CA monomers. To minimize the protein-ligand steric clash, the I66 side chain in the M66I-GS-6207 complex switches to a higher free energy conformation from the one adopted in the apo M66I. In contrast, the binding of GS-6207 to the wild-type CA does not lead to any significant M66 conformational change. Based on an analysis that decomposes the absolute binding free energy into contributions from two receptor conformational states, it appears that it is the free energy cost of side chain reorganization rather than the reduced protein-ligand interaction that is largely responsible for the drug resistance against GS-6207. | ||
| + | |||
| + | Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation.,Sun Q, Levy RM, Kirby KA, Wang Z, Sarafianos SG, Deng N Viruses. 2021 May 15;13(5). pii: v13050920. doi: 10.3390/v13050920. PMID:34063519<ref>PMID:34063519</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7m9f" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human immunodeficiency virus 1]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Kirby KA]] | [[Category: Kirby KA]] | ||
[[Category: Sarafianos SG]] | [[Category: Sarafianos SG]] | ||
Revision as of 16:07, 18 October 2023
Structure of the wild-type native full-length HIV-1 capsid protein in complex with ZW-1261
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