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

Matthew Mealka, Nicole A. Sierra, Diego Avellaneda Matteo, Elene Albekioni, Rachel Khoury, Timothy Mai, Brittany M. Conley, Nalani J. Coleman, Kaitlyn A. Sabo, Elizabeth A. Komives, Andrey A. Bobkov, Andrew L. Cooksy, Steve Silletti, Jamie M. Schiffer, Tom Huxford and Christal D. Sohl ()
Additional contact information
Matthew Mealka: San Diego State University
Nicole A. Sierra: San Diego State University
Diego Avellaneda Matteo: San Diego State University
Elene Albekioni: San Diego State University
Rachel Khoury: San Diego State University
Timothy Mai: San Diego State University
Brittany M. Conley: San Diego State University
Nalani J. Coleman: San Diego State University
Kaitlyn A. Sabo: San Diego State University
Elizabeth A. Komives: University of California San Diego
Andrey A. Bobkov: Sanford Burnham Prebys Medical Discovery Institute
Andrew L. Cooksy: San Diego State University
Steve Silletti: University of California San Diego
Jamie M. Schiffer: Vividion Therapeutics
Tom Huxford: San Diego State University
Christal D. Sohl: San Diego State University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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 unusually preserves conventional activity while catalyzing robust oncometabolite production, allowing an opportunity to compare these reaction mechanisms within a single active site. Here, we employ static and dynamic structural methods and observe that, compared to R132H, the R132Q active site adopts 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 reveals 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.

Date: 2024
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-48277-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48277-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-48277-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().