4XRO

Disulfide stabilized HIV-1 CA hexamer 4mut (S41A, Q67H, V165I, L172I)

4XRO の概要

• エントリーDOI: 10.2210/pdb4xro/pdb
• 分子名称: Capsid protein p24 (2 entities in total)
• 機能のキーワード: viral protein, capsid
• 由来する生物種: Human immunodeficiency virus type 1 group M subtype B (isolate NY5) (HIV-1)
• 細胞内の位置: Gag polyprotein: Host cell membrane; Lipid- anchor . Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion : P12493
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25469.32

構造登録者

Price, A.J.,James, L.C. (登録日: 2015-01-21, 公開日: 2015-07-15, 最終更新日: 2024-10-23)

主引用文献

Zhou, J.,Price, A.J.,Halambage, U.D.,James, L.C.,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., 89:9068-9079, 2015

PubMed Abstract: 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.

PubMed: 26109731
DOI: 10.1128/JVI.00340-15

実験手法

X-RAY DIFFRACTION (2.01 Å)