|
|
| (3 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| | + | |
| | ==Disulfide stabilized HIV-1 CA hexamer 4mut (S41A, Q67H, V165I, L172I) in complex with PF-3450074== | | ==Disulfide stabilized HIV-1 CA hexamer 4mut (S41A, Q67H, V165I, L172I) in complex with PF-3450074== |
| - | <StructureSection load='4xrq' size='340' side='right' caption='[[4xrq]], [[Resolution|resolution]] 1.95Å' scene=''> | + | <StructureSection load='4xrq' size='340' side='right'caption='[[4xrq]], [[Resolution|resolution]] 1.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4xrq]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XRQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XRQ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4xrq]] 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=4XRQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XRQ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1B0:N-METHYL-NALPHA-[(2-METHYL-1H-INDOL-3-YL)ACETYL]-N-PHENYL-L-PHENYLALANINAMIDE'>1B0</scene></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]] 1.95Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4xro|4xro]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1B0:N-METHYL-NALPHA-[(2-METHYL-1H-INDOL-3-YL)ACETYL]-N-PHENYL-L-PHENYLALANINAMIDE'>1B0</scene></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=4xrq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xrq OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4xrq RCSB], [http://www.ebi.ac.uk/pdbsum/4xrq PDBsum]</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=4xrq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xrq OCA], [https://pdbe.org/4xrq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xrq RCSB], [https://www.ebi.ac.uk/pdbsum/4xrq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xrq ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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). | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 17: |
Line 18: |
| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4xrq" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: James, L C]] | + | [[Category: Human immunodeficiency virus 1]] |
| - | [[Category: Price, A J]] | + | [[Category: Large Structures]] |
| - | [[Category: Capsid]] | + | [[Category: James LC]] |
| - | [[Category: Inhibitor]] | + | [[Category: Price AJ]] |
| - | [[Category: Viral protein]]
| + | |
| Structural highlights
Function
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).
Publication Abstract from PubMed
During HIV-1 infection of cells, the viral capsid plays critical roles in reverse transcription and nuclear entry of the virus. The capsid-targeting small molecule PF74 inhibits HIV-1 at early stages of infection. HIV-1 resistance to PF74 is complex, requiring multiple amino acid substitutions in the viral CA protein. Here we report the identification and analysis of a novel PF74-resistant mutant encoding amino acid changes in both domains of CA, three of which are near the pocket where PF74 binds. Interestingly, the mutant virus retained partial PF74 binding, and its replication was stimulated by the compound. The mutant capsid structure was not significantly perturbed by binding of PF74; rather, the mutations inhibited capsid interactions with CPSF6 and Nup153 and altered HIV-1 dependence on these host factors and on TNPO3. Moreover, the replication of the mutant virus was markedly impaired in activated primary CD4+ T cells and macrophages. Our results suggest that HIV-1 escapes a capsid-targeting small molecule inhibitor by altering the virus's dependence on host factors normally required for entry into the nucleus. They further imply that clinical resistance to inhibitors targeting the PF74 binding pocket is likely to be strongly limited by functional constraints on HIV-1 evolution. IMPORTANCE: The HIV-1 capsid plays critical roles in early steps of infection and is an attractive target for therapy. Here we show that selection for resistance to a capsid-targeting small molecule inhibitor can result in viral dependence on the compound. The mutant virus was debilitated in primary T cells and macrophages---cellular targets of infection in vivo. The mutations also altered the virus's dependence on cellular factors that are normally required for HIV-1 entry into the nucleus. This work provides new information regarding mechanisms of HIV-1 resistance that should be useful in efforts to develop clinically useful drugs targeting the HIV-1 capsid.
HIV-1 Resistance to the Capsid-Targeting Inhibitor PF74 Results in Altered Dependence on Host Factors Required for Virus Nuclear Entry.,Zhou J, Price AJ, Halambage UD, James LC, Aiken C J Virol. 2015 Jun 24. pii: JVI.00340-15. PMID:26109731[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zhou J, Price AJ, Halambage UD, James LC, Aiken C. HIV-1 Resistance to the Capsid-Targeting Inhibitor PF74 Results in Altered Dependence on Host Factors Required for Virus Nuclear Entry. J Virol. 2015 Jun 24. pii: JVI.00340-15. PMID:26109731 doi:http://dx.doi.org/10.1128/JVI.00340-15
|
