5OU2

M. thermoresistible IMPDH in complex with IMP and Compound 2 (NMR744)

5OU2 の概要

• エントリーDOI: 10.2210/pdb5ou2/pdb
• 分子名称: Inosine-5'-monophosphate dehydrogenase,Inosine-5'-monophosphate dehydrogenase, INOSINIC ACID, 4-(4-bromophenyl)-1H-imidazole, ... (4 entities in total)
• 機能のキーワード: complex, fragment, impdh, oxidoreductase
• 由来する生物種: Mycobacterium thermoresistibile (strain ATCC 19527 / DSM 44167 / CIP 105390 / JCM 6362 / NCTC 10409 / 316); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40648.82

構造登録者

Ascher, D.B.,Pacitto, A.,Blundell, T.L. (登録日: 2017-08-23, 公開日: 2018-03-28, 最終更新日: 2024-05-08)

主引用文献

Trapero, A.,Pacitto, A.,Singh, V.,Sabbah, M.,Coyne, A.G.,Mizrahi, V.,Blundell, T.L.,Ascher, D.B.,Abell, C.
Fragment-Based Approach to Targeting Inosine-5'-monophosphate Dehydrogenase (IMPDH) from Mycobacterium tuberculosis.
J. Med. Chem., 61:2806-2822, 2018

PubMed Abstract: Tuberculosis (TB) remains a major cause of mortality worldwide, and improved treatments are needed to combat emergence of drug resistance. Inosine 5'-monophosphate dehydrogenase (IMPDH), a crucial enzyme required for de novo synthesis of guanine nucleotides, is an attractive TB drug target. Herein, we describe the identification of potent IMPDH inhibitors using fragment-based screening and structure-based design techniques. Screening of a fragment library for Mycobacterium thermoresistible ( Mth) IMPDH ΔCBS inhibitors identified a low affinity phenylimidazole derivative. X-ray crystallography of the Mth IMPDH ΔCBS-IMP-inhibitor complex revealed that two molecules of the fragment were bound in the NAD binding pocket of IMPDH. Linking the two molecules of the fragment afforded compounds with more than 1000-fold improvement in IMPDH affinity over the initial fragment hit.

PubMed: 29547284
DOI: 10.1021/acs.jmedchem.7b01622

実験手法

X-RAY DIFFRACTION (1.45 Å)