4J93

Crystal Structure of the N-Terminal Domain of HIV-1 Capsid in Complex With Inhibitor BI-1

4J93 の概要

• エントリーDOI: 10.2210/pdb4j93/pdb
• 関連するPDBエントリー: 4E91 4E92
• 分子名称: Gag protein, 4-{2-[5-(3-chlorophenyl)-1H-pyrazol-4-yl]-1-[3-(1H-imidazol-1-yl)propyl]-1H-benzimidazol-5-yl}benzoic acid, (4S)-3-phenyl-4-(pyridin-3-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one, ... (4 entities in total)
• 機能のキーワード: structural protein capsid, viral protein, viral protein-viral protein inhibitor complex, viral protein/viral protein inhibitor
• 由来する生物種: Human immunodeficiency virus 1
• 細胞内の位置: Matrix protein p17: Virion (By similarity). Virion (By similarity): Q79791
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 17003.85

構造登録者

Lemke, C.T. (登録日: 2013-02-15, 公開日: 2013-07-10, 最終更新日: 2024-02-28)

主引用文献

Lamorte, L.,Titolo, S.,Lemke, C.T.,Goudreau, N.,Mercier, J.F.,Wardrop, E.,Shah, V.B.,von Schwedler, U.K.,Langelier, C.,Banik, S.S.,Aiken, C.,Sundquist, W.I.,Mason, S.W.
Discovery of Novel Small-Molecule HIV-1 Replication Inhibitors That Stabilize Capsid Complexes.
Antimicrob.Agents Chemother., 57:4622-4631, 2013

PubMed Abstract: The identification of novel antiretroviral agents is required to provide alternative treatment options for HIV-1-infected patients. The screening of a phenotypic cell-based viral replication assay led to the identification of a novel class of 4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (pyrrolopyrazolone) HIV-1 inhibitors, exemplified by two compounds: BI-1 and BI-2. These compounds inhibited early postentry stages of viral replication at a step(s) following reverse transcription but prior to 2 long terminal repeat (2-LTR) circle formation, suggesting that they may block nuclear targeting of the preintegration complex. Selection of viruses resistant to BI-2 revealed that substitutions at residues A105 and T107 within the capsid (CA) amino-terminal domain (CANTD) conferred high-level resistance to both compounds, implicating CA as the antiviral target. Direct binding of BI-1 and/or BI-2 to CANTD was demonstrated using isothermal titration calorimetry and nuclear magnetic resonance (NMR) chemical shift titration analyses. A high-resolution crystal structure of the BI-1:CANTD complex revealed that the inhibitor bound within a recently identified inhibitor binding pocket (CANTD site 2) between CA helices 4, 5, and 7, on the surface of the CANTD, that also corresponds to the binding site for the host factor CPSF-6. The functional consequences of BI-1 and BI-2 binding differ from previously characterized inhibitors that bind the same site since the BI compounds did not inhibit reverse transcription but stabilized preassembled CA complexes. Hence, this new class of antiviral compounds binds CA and may inhibit viral replication by stabilizing the viral capsid.

PubMed: 23817385
DOI: 10.1128/AAC.00985-13

実験手法

X-RAY DIFFRACTION (1.74 Å)