4QNB

Disulfide stabilized HIV-1 CA hexamer in complex with PHENYL-L-PHENYLALANINAMIDE inhibitor

4QNB の概要

• エントリーDOI: 10.2210/pdb4qnb/pdb
• 関連するPDBエントリー: 3h47
• 分子名称: CAPSID PROTEIN P24, N-METHYL-NALPHA-[(2-METHYL-1H-INDOL-3-YL)ACETYL]-N-PHENYL-L-PHENYLALANINAMIDE (3 entities in total)
• 機能のキーワード: capsid protein, disulfide crosslink, viral protein, viral protein-inhibitor complex, viral protein/inhibitor
• 由来する生物種: Human immunodeficiency virus type 1 (NEW YORK-5 ISOLATE) (HIV-1)
• 細胞内の位置: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor . Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P12497
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25886.79

構造登録者

Pornillos, O. (登録日: 2014-06-17, 公開日: 2014-12-31, 最終更新日: 2024-10-30)

主引用文献

Bhattacharya, A.,Alam, S.L.,Fricke, T.,Zadrozny, K.,Sedzicki, J.,Taylor, A.B.,Demeler, B.,Pornillos, O.,Ganser-Pornillos, B.K.,Diaz-Griffero, F.,Ivanov, D.N.,Yeager, M.
Structural basis of HIV-1 capsid recognition by PF74 and CPSF6.
Proc.Natl.Acad.Sci.USA, 111:18625-18630, 2014

PubMed Abstract: Upon infection of susceptible cells by HIV-1, the conical capsid formed by ∼250 hexamers and 12 pentamers of the CA protein is delivered to the cytoplasm. The capsid shields the RNA genome and proteins required for reverse transcription. In addition, the surface of the capsid mediates numerous host-virus interactions, which either promote infection or enable viral restriction by innate immune responses. In the intact capsid, there is an intermolecular interface between the N-terminal domain (NTD) of one subunit and the C-terminal domain (CTD) of the adjacent subunit within the same hexameric ring. The NTD-CTD interface is critical for capsid assembly, both as an architectural element of the CA hexamer and pentamer and as a mechanistic element for generating lattice curvature. Here we report biochemical experiments showing that PF-3450074 (PF74), a drug that inhibits HIV-1 infection, as well as host proteins cleavage and polyadenylation specific factor 6 (CPSF6) and nucleoporin 153 kDa (NUP153), bind to the CA hexamer with at least 10-fold higher affinities compared with nonassembled CA or isolated CA domains. The crystal structure of PF74 in complex with the CA hexamer reveals that PF74 binds in a preformed pocket encompassing the NTD-CTD interface, suggesting that the principal inhibitory target of PF74 is the assembled capsid. Likewise, CPSF6 binds in the same pocket. Given that the NTD-CTD interface is a specific molecular signature of assembled hexamers in the capsid, binding of NUP153 at this site suggests that key features of capsid architecture remain intact upon delivery of the preintegration complex to the nucleus.

PubMed: 25518861
DOI: 10.1073/pnas.1419945112

実験手法

X-RAY DIFFRACTION (1.996 Å)