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

Matthew Mealka1, Nicole A Sierra1, Diego Avellaneda Matteo1

  • 1Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA.

Research Square
|March 11, 2024
PubMed

Insights

Mutations in human isocitrate dehydrogenase 1 (IDH1) cause cancer by creating a new function that produces an oncometabolite. Structural analysis reveals how IDH1 R132Q mutant remodels its active site for enhanced activity, impacting therapeutic strategies.

Area of Science:

  • Biochemistry
  • Cancer Biology
  • Structural Biology

Background:

  • Mutations in human isocitrate dehydrogenase 1 (IDH1) are drivers of various cancers.
  • These mutations confer a neomorphic (cancer-driving) activity, generating an oncometabolite.
  • Mechanistic differences among IDH1 mutants remain poorly understood.

Approach:

  • Utilized static and dynamic structural methods to investigate IDH1 mutants.
  • Compared the R132Q mutant, which retains conventional activity and produces oncometabolites, with the R132H mutant.
  • Focused on active site conformation, substrate binding, and hydride transfer dynamics.

Key Points:

  • The IDH1 R132Q active site adopts a conformation optimized for catalysis, surpassing R132H.
  • This remodeling enhances both conventional and neomorphic enzymatic activities.
  • Identified potential mechanisms of resistance to targeted IDH1 inhibitors.

Conclusions:

  • Elucidated mechanistic differences between IDH1 R132Q and R132H mutants.
  • Provided insights into active site remodeling and its impact on enzyme function.
  • Highlighted structural features for developing more selective IDH1 inhibitors.
Keywords:
Enzyme mechanismHDX-MSIDH1oncometabolitestructure-function relationships

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