4JTY

Crystal structure of HCV NS5B polymerase with COMPOUND 2

4JTY の概要

• エントリーDOI: 10.2210/pdb4jty/pdb
• 関連するPDBエントリー: 3MWV 4JTW 4JTZ 4JU1 4JU2 4JU3 4JU4 4JU6 4JU7 4JVQ 4JY0 4JY1
• 分子名称: Genome polyprotein, GLYCEROL, 3-{[4-oxo-1-(2,4,6-trifluorobenzyl)-1,4-dihydroquinazolin-6-yl]oxy}-2-(trifluoromethyl)benzamide, ... (5 entities in total)
• 機能のキーワード: rna-directed rna polymerase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Hepatitis C virus (HCV)
• 細胞内の位置: Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein (By similarity). Core protein p19: Virion (By similarity). Envelope glycoprotein E1: Virion membrane; Single-pass type I membrane protein (Potential). Envelope glycoprotein E2: Virion membrane; Single-pass type I membrane protein (Potential). p7: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Protease NS2-3: Host endoplasmic reticulum membrane; Multi-pass membrane protein (Potential). Serine protease NS3: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). Non-structural protein 4A: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential). Non-structural protein 4B: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Non-structural protein 5A: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). RNA-directed RNA polymerase: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential): O92972
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 129790.79

構造登録者

Coulombe, R. (登録日: 2013-03-24, 公開日: 2013-07-03, 最終更新日: 2023-09-20)

主引用文献

Hucke, O.,Coulombe, R.,Bonneau, P.,Bertrand-Laperle, M.,Brochu, C.,Gillard, J.,Joly, M.A.,Landry, S.,Lepage, O.,Llinas-Brunet, M.,Pesant, M.,Poirier, M.,Poirier, M.,McKercher, G.,Marquis, M.,Kukolj, G.,Beaulieu, P.L.,Stammers, T.A.
Molecular Dynamics Simulations and Structure-Based Rational Design Lead to Allosteric HCV NS5B Polymerase Thumb Pocket 2 Inhibitor with Picomolar Cellular Replicon Potency.
J.Med.Chem., 57:1932-1943, 2014

PubMed Abstract: The design and preliminary SAR of a new series of 1H-quinazolin-4-one (QAZ) allosteric HCV NS5B thumb pocket 2 (TP-2) inhibitors was recently reported. To support optimization efforts, a molecular dynamics (MD) based modeling workflow was implemented, providing information on QAZ binding interactions with NS5B. This approach predicted a small but critical ligand-binding induced movement of a protein backbone region which increases the pocket size and improves access to the backbone carbonyl groups of Val 494 and Pro 495. This localized backbone shift was consistent with key SAR results and was subsequently confirmed by X-ray crystallography. The MD protocol guided the design of inhibitors, exploiting novel H-bond interactions with the two backbone carbonyl groups, leading to the first thumb pocket 2 NS5B inhibitor with picomolar antiviral potency in genotype (gt) 1a and 1b replicons (EC50 = 120 and 110 pM, respectively) and with EC50 ≤ 80 nM against gt 2-6.

PubMed: 23773186
DOI: 10.1021/jm4004522

実験手法

X-RAY DIFFRACTION (2.6 Å)