title: 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.
authors.affiliation: Computational Biology Lab, Department of Biotechnology, School of Bio Sciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India. aradhanarajendran@gmail.com.
authors.forename: Vidya
authors.initials: V
authors.lastname: Rajendran
mesh_terms: D001665:Binding Sites; D006801:Humans; D006860:Hydrogen Bonding; D007521:Isocitrate Dehydrogenase / Q000737:chemistry* / Q000235:genetics*; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human