6BKX

Novel Modes of Inhibition of Wild-Type IDH1: Direct Covalent Modification of His315 with Cmpd1

Summary for 6BKX

• Entry DOI: 10.2210/pdb6bkx/pdb
• Descriptor: Isocitrate dehydrogenase [NADP] cytoplasmic, CALCIUM ION, ISOCITRIC ACID, ... (5 entities in total)
• Functional Keywords: dehydrogenase, inhibitor, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 146200.07

Authors

Jakob, C.G.,Qiu, W. (deposition date: 2017-11-09, release date: 2018-07-25, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.65 Å)