7M9F

Structure of the wild-type native full-length HIV-1 capsid protein in complex with ZW-1261

7M9F の概要

• エントリーDOI: 10.2210/pdb7m9f/pdb
• 分子名称: HIV-1 capsid protein, N-(4-chlorophenyl)-Nalpha-[(5-hydroxy-1H-indol-3-yl)acetyl]-N-methyl-L-phenylalaninamide, IODIDE ION, ... (4 entities in total)
• 機能のキーワード: hiv-1 capsid protein, hexamer, ca-targeting antiviral, viral protein
• 由来する生物種: Human immunodeficiency virus 1
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26726.89

構造登録者

Kirby, K.A.,Sarafianos, S.G. (登録日: 2021-03-31, 公開日: 2022-04-06, 最終更新日: 2024-11-20)

主引用文献

Sun, Q.,Levy, R.M.,Kirby, K.A.,Wang, Z.,Sarafianos, S.G.,Deng, N.
Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation.
Viruses, 13:-, 2021

PubMed Abstract: While drug resistance mutations can often be attributed to the loss of direct or solvent-mediated protein-ligand interactions in the drug-mutant complex, in this study we show that a resistance mutation for the picomolar HIV-1 capsid (CA)-targeting antiviral (GS-6207) is mainly due to the free energy cost of the drug-induced protein side chain reorganization in the mutant protein. Among several mutations, M66I causes the most suppression of the GS-6207 antiviral activity (up to ~84,000-fold), and only 83- and 68-fold reductions for PF74 and ZW-1261, respectively. To understand the molecular basis of this drug resistance, we conducted molecular dynamics free energy simulations to study the structures, energetics, and conformational free energy landscapes involved in the inhibitors binding at the interface of two CA monomers. To minimize the protein-ligand steric clash, the I66 side chain in the M66I-GS-6207 complex switches to a higher free energy conformation from the one adopted in the apo M66I. In contrast, the binding of GS-6207 to the wild-type CA does not lead to any significant M66 conformational change. Based on an analysis that decomposes the absolute binding free energy into contributions from two receptor conformational states, it appears that it is the free energy cost of side chain reorganization rather than the reduced protein-ligand interaction that is largely responsible for the drug resistance against GS-6207.

PubMed: 34063519
DOI: 10.3390/v13050920

実験手法

X-RAY DIFFRACTION (2.7 Å)