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

Autor:	Mealka M; Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA., Sierra NA; Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA., Matteo DA; Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA., Albekioni E; Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA., Khoury R; Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA., Mai T; Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA., Conley BM; Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA., Coleman NJ; Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA., Sabo KA; Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA., Komives EA; Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA, USA., Bobkov AA; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA USA., Cooksy AL; Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA., Silletti S; Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA, USA., Schiffer JM; Vividion Therapeutics, San Diego, CA, USA., Huxford T; Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA., Sohl CD; Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2024 Feb 23. Date of Electronic Publication: 2024 Feb 23.
DOI:	10.21203/rs.3.rs-3889456/v1
Abstrakt:	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. Competing Interests: Competing interests The authors declare that they have no conflicts of interest. Additional Declarations: There is NO Competing Interest.
Databáze:	MEDLINE
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