# Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms

## TL;DR

This paper explores how different mutations in the IDH1 enzyme affect its activity and may lead to cancer and resistance to drugs.

## Contribution

The study reveals how the R132Q IDH1 mutant maintains conventional and neomorphic activity through active site remodeling.

## Key findings

- The R132Q mutant IDH1 has an active site conformation optimized for catalysis and substrate binding.
- Active site remodeling in R132Q may explain resistance to IDH1 inhibitors.
- The findings highlight structural differences between R132Q and R132H mutants.

## Abstract

Mutations in human isocitrate dehydrogenase 1 (IDH1) drive tumor formation in a variety of cancers by replacing its conventional activity with a neomorphic activity that generates an oncometabolite. Little is understood of the mechanistic differences among tumor-driving IDH1 mutants. We previously reported that the R132Q mutant uniquely preserves conventional activity while catalyzing robust oncometabolite production, allowing an opportunity to compare these reaction mechanisms within a single active site. Here, we employed static and dynamic structural methods and found that, compared to R132H, the R132Q active site adopted a conformation primed for catalysis with optimized substrate binding and hydride transfer to drive improved conventional and neomorphic activity over R132H. This active site remodeling revealed a possible mechanism of resistance to selective mutant IDH1 therapeutic inhibitors. This work enhances our understanding of fundamental IDH1 mechanisms while pinpointing regions for improving inhibitor selectivity.