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 mar 2016
Accepted
03 máj 2016
First published
03 máj 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

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Spotlight

Advertisements