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

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Biology

Background:

• Mutations in human isocitrate dehydrogenase 1 (IDH1) are drivers of various cancers.
• IDH1 mutations confer neomorphic activity, producing an oncometabolite that promotes tumor formation.
• Mechanistic differences among IDH1 mutants remain poorly understood.

Purpose of the Study:

• To investigate the mechanistic differences between tumor-driving IDH1 mutants.
• To compare the reaction mechanisms of the R132Q mutant, which retains conventional activity while producing oncometabolites, with other mutants.
• To understand how IDH1 mutations contribute to cancer and therapeutic resistance.

Main Methods:

• Utilized static and dynamic structural methods.
• Analyzed the active site conformation and substrate binding.
• Assessed hydride transfer efficiency.

Main Results:

• The R132Q IDH1 active site adopts a conformation optimized for catalysis.
• Compared to the R132H mutant, R132Q exhibits enhanced substrate binding and hydride transfer.
• R132Q demonstrates improved conventional and neomorphic activity over R132H.
• Observed active site remodeling in R132Q that may explain resistance to IDH1 inhibitors.

Conclusions:

• The structural plasticity of the IDH1 active site influences its catalytic activities.
• Understanding IDH1 active site remodeling is crucial for developing effective cancer therapies.
• This study provides insights into IDH1 mechanisms and identifies targets for improving inhibitor selectivity.