Issue 7, 2016

Structural analysis of oncogenic mutation of isocitrate dehydrogenase 1

Abstract

Arginine to histidine mutation at position 132 (R132H) in isocitrate dehydrogenase 1 (IDH1) led to reduced affinity of the respective enzymes for isocitrate and increased affinity for α-ketoglutarate (AKG) and NADPH. This phenomenon retarded oxidative decarboxylation of isocitrate to AKG and conferred a novel enzymatic activity that facilitated the reduction of AKG to D-2-hydroxyglutarate (D-2HG). The loss of isocitrate utilization and gain of 2HG production from IDH1 R132H had been taken up as a fundamental problem and to solve this, structural biology approaches were adopted. Interaction analysis was carried out to investigate the IDH1 substrate binding environment. The altered behaviour of mutant and native IDH1 in interaction analysis was explored by performing long-term molecular dynamics simulations (∼300 ns). This study reports a comprehensive atomic behaviour of the gain-of-function mutation (R132H) in the IDH1 enzyme which in turn provides a direction towards new therapeutics.

Graphical abstract: Structural analysis of oncogenic mutation of isocitrate dehydrogenase 1

Article information

Article type
Paper
Submitted
09 Mac 2016
Accepted
03 Mei 2016
First published
03 Mei 2016

Mol. BioSyst., 2016,12, 2276-2287

Structural analysis of oncogenic mutation of isocitrate dehydrogenase 1

V. Rajendran, Mol. BioSyst., 2016, 12, 2276 DOI: 10.1039/C6MB00182C

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