4K4R

TL-3 inhibited Trp6Ala HIV Protease with 1-bromo-2-napthoic acid bound in exosite

4K4R の概要

• エントリーDOI: 10.2210/pdb4k4r/pdb
• 関連するPDBエントリー: 4K4P 4K4Q
• 関連するBIRD辞書のPRD_ID: PRD_000434
• 分子名称: Gag-Pol polyprotein, DIMETHYL SULFOXIDE, 1-bromonaphthalene-2-carboxylic acid, ... (7 entities in total)
• 機能のキーワード: fragment binding, exosite, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Human immunodeficiency virus type 1 (HIV-1)
• 細胞内の位置: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P12499
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 23312.69

構造登録者

Tiefenbrunn, T.,Stout, C.D. (登録日: 2013-04-12, 公開日: 2013-09-18, 最終更新日: 2024-02-28)

主引用文献

Tiefenbrunn, T.,Forli, S.,Happer, M.,Gonzalez, A.,Tsai, Y.,Soltis, M.,Elder, J.H.,Olson, A.J.,Stout, C.D.
Crystallographic Fragment-Based Drug Discovery: Use of a Brominated Fragment Library Targeting HIV Protease.
Chem.Biol.Drug Des., 83:141-148, 2014

PubMed Abstract: A library of 68 brominated fragments was screened against a new crystal form of inhibited HIV-1 protease in order to probe surface sites in soaking experiments. Often, fragments are weak binders with partial occupancy, resulting in weak, difficult-to-fit electron density. The use of a brominated fragment library addresses this challenge, as bromine can be located unequivocally via anomalous scattering. Data collection was carried out in an automated fashion using AutoDrug at SSRL. Novel hits were identified in the known surface sites: 3-bromo-2,6-dimethoxybenzoic acid (Br6) in the flap site and 1-bromo-2-naphthoic acid (Br27) in the exosite, expanding the chemistry of known fragments for development of higher affinity potential allosteric inhibitors. At the same time, mapping the binding sites of a number of weaker binding Br-fragments provides further insight into the nature of these surface pockets.

PubMed: 23998903
DOI: 10.1111/cbdd.12227

実験手法

X-RAY DIFFRACTION (1.8 Å)