5HRP

HIV Integrase Catalytic Domain containing F185K + A124T mutations complexed with GSK0002

5HRP の概要

• エントリーDOI: 10.2210/pdb5hrp/pdb
• 関連するPDBエントリー: 5HOT 5HRN 5HRR 5HRS
• 分子名称: Integrase, CACODYLATE ION, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: viral dna integration, dna binding, ledgf binding, viral protein, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Human immunodeficiency virus 1 (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 : P04585
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19348.56

構造登録者

Nolte, R.T. (登録日: 2016-01-24, 公開日: 2016-12-14, 最終更新日: 2024-03-06)

主引用文献

Gupta, K.,Turkki, V.,Sherrill-Mix, S.,Hwang, Y.,Eilers, G.,Taylor, L.,McDanal, C.,Wang, P.,Temelkoff, D.,Nolte, R.T.,Velthuisen, E.,Jeffrey, J.,Van Duyne, G.D.,Bushman, F.D.
Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase.
PLoS Biol., 14:e1002584-e1002584, 2016

PubMed Abstract: The allosteric inhibitors of integrase (termed ALLINIs) interfere with HIV replication by binding to the viral-encoded integrase (IN) protein. Surprisingly, ALLINIs interfere not with DNA integration but with viral particle assembly late during HIV replication. To investigate the ALLINI inhibitory mechanism, we crystallized full-length HIV-1 IN bound to the ALLINI GSK1264 and determined the structure of the complex at 4.4 Å resolution. The structure shows GSK1264 buried between the IN C-terminal domain (CTD) and the catalytic core domain. In the crystal lattice, the interacting domains are contributed by two different dimers so that IN forms an open polymer mediated by inhibitor-bridged contacts; the N-terminal domains do not participate and are structurally disordered. Engineered amino acid substitutions at the inhibitor interface blocked ALLINI-induced multimerization. HIV escape mutants with reduced sensitivity to ALLINIs commonly altered amino acids at or near the inhibitor-bound interface, and these substitutions also diminished IN multimerization. We propose that ALLINIs inhibit particle assembly by stimulating inappropriate polymerization of IN via interactions between the catalytic core domain and the CTD and that understanding the interface involved offers new routes to inhibitor optimization.

PubMed: 27935939
DOI: 10.1371/journal.pbio.1002584

実験手法

X-RAY DIFFRACTION (1.81 Å)