Protein arginine methylation is an important post-translational modification involved in cellular processes, including signaling, RNA processing, and gene transcription. The arginine methylation enzyme of interest, protein arginine methyltransferase 7 (PRMT7), exclusively generates the first turnover product, monomethylated arginine (MMA), but neither of the second turnover products, asymmetric dimethylated arginine (ADMA) and symmetric dimethylated arginine (SDMA). However, it remains unclear how PRMT7 product specificity is regulated, an important exploit since PRMTs have been implicated in many with different types of cancer. It opens a big question, how PRMT7 product specificity is regulated and which active site base governs the proton abstraction in the S<sub>N</sub>2 mechanism? Computational and experimental mutagenesis work has been performed and it was determined that single amino acid mutations, i.e., Phe71Ile, in the PRMT7 active site can enable the enzyme to perform a second turnover and that Glu172 may be acting as the base. However, the mutations Phe71Ala and Phe71Ser did not yield the second turnover. Combined quantum mechanical and molecular mechanical calculations and molecular dynamics simulations (QM/MM/MD) that employed free energy perturbation methods have been used to help elucidate the origin of the product specificity in both WT and mutant PRMT7 enzymes. Additional binding pocket interactions and the role that active site residue Gln329 plays in product specificity and in the activity of PRMT7 was also investigated and will be discussed.

Directing product specificity of type-III PRMT7 to type-I/II

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.