Transition state mimics are valuable mechanistic probes for structural studies with the arginine methyltransferase CARM1

Matthijs van Haren , Nils Marechal (1, 2) , Nathalie Troffer-Charlier (1, 2) , Agostino Cianciulli , Gianluca Sbardella , Jean Cavarelli (1, 2) , Nathaniel Martin

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
2 IGBMC - Institut de génétique et biologie moléculaire et cellulaire

Coactivator associated arginine methyltransferase 1 (CARM1) is a member of the protein arginine methyltransferase (PRMT) family and methylates a range of proteins in eukaryotic cells. Overexpression of CARM1 is implicated in a number of cancers, and it is therefore seen as a potential therapeutic target. Peptide sequences derived from the well-defined CARM1 substrate poly(A)-binding protein 1 (PABP1) were covalently linked to an adenosine moiety as in the AdoMet cofactor to generate transition state mimics. These constructs were found to be potent CARM1 inhibitors and also formed stable complexes with the enzyme. High-resolution crystal structures of CARM1 in complex with these compounds confirm a mode of binding that is indeed reflective of the transition state at the CARM1 active site. Given the transient nature of PRMT-substrate complexes, such transition state mimics represent valuable chemical tools for structural studies aimed at deciphering the regulation of arginine methylation mediated by the family of arginine methyltransferases.

Mots clés: Carm1; Prmt; cocrystal structures; protein arginine N-methyltransferase; transition state mimics

Domaines: Biochimie, Biologie Moléculaire

Matthijs van Haren, Nils Marechal, Nathalie Troffer-Charlier, Agostino Cianciulli, Gianluca Sbardella, et al.. Transition state mimics are valuable mechanistic probes for structural studies with the arginine methyltransferase CARM1. Proceedings of the National Academy of Sciences of the United States of America, 2017, 114 (14), pp.3625-3630. ⟨10.1073/pnas.1618401114⟩. ⟨hal-03680438⟩