6BL0

Novel Modes of Inhibition of Wild-Type IDH1:Direct Covalent Modification of His315 with Cmpd11

6BL0 の概要

• エントリーDOI: 10.2210/pdb6bl0/pdb
• 分子名称: Isocitrate dehydrogenase [NADP] cytoplasmic, MAGNESIUM ION, ISOCITRIC ACID, ... (6 entities in total)
• 機能のキーワード: dehydrogenase, inhibitor, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 147009.77

構造登録者

Jakob, C.G.,Qiu, W. (登録日: 2017-11-09, 公開日: 2018-07-25, 最終更新日: 2024-11-20)

主引用文献

Jakob, C.G.,Upadhyay, A.K.,Donner, P.L.,Nicholl, E.,Addo, S.N.,Qiu, W.,Ling, C.,Gopalakrishnan, S.M.,Torrent, M.,Cepa, S.P.,Shanley, J.,Shoemaker, A.R.,Sun, C.C.,Vasudevan, A.,Woller, K.R.,Shotwell, J.B.,Shaw, B.,Bian, Z.,Hutti, J.E.
Novel Modes of Inhibition of Wild-Type Isocitrate Dehydrogenase 1 (IDH1): Direct Covalent Modification of His315.
J. Med. Chem., 61:6647-6657, 2018

PubMed Abstract: IDH1 plays a critical role in a number of metabolic processes and serves as a key source of cytosolic NADPH under conditions of cellular stress. However, few inhibitors of wild-type IDH1 have been reported. Here we present the discovery and biochemical characterization of two novel inhibitors of wild-type IDH1. In addition, we present the first ligand-bound crystallographic characterization of these novel small molecule IDH1 binding pockets. Importantly, the NADPH competitive α,β-unsaturated enone 1 makes a unique covalent linkage through active site H315. As few small molecules have been shown to covalently react with histidine residues, these data support the potential utility of an underutilized strategy for reversible covalent small molecule design.

PubMed: 30004704
DOI: 10.1021/acs.jmedchem.8b00305

実験手法

X-RAY DIFFRACTION (2.17 Å)