Structural Insights into Ternary Complex Formation of Human CARM1 with Various Substrates

• Published in: ACS chemical biology 2016-03, Vol.11 (3), p.763-771
• Main Authors: Boriack-Sjodin, P. Ann, Jin, Lei, Jacques, Suzanne L, Drew, Allison, Sneeringer, Chris, Scott, Margaret Porter, Moyer, Mikel P, Ribich, Scott, Moradei, Oscar, Copeland, Robert A
• Format: Article
• Language: English
• Subjects: Binding Sites; Cell Line; Crystallography, X-Ray; Gene Expression Regulation, Enzymologic; Humans; Models, Molecular; Protein Conformation; Protein-Arginine N-Methyltransferases - chemistry; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; Substrate Specificity
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.5b00773

Coactivator-associated arginine methyltransferase 1 (CARM1) is a protein arginine N-methyltransferase (PRMT) enzyme that has been implicated in a variety of cancers. CARM1 is known to methylate histone H3 and nonhistone substrates. To date, several crystal structures of CARM1 have been solved, including structures with small molecule inhibitors, but no ternary structures with nucleoside and peptide substrates have been reported. Here, the crystal structures of human CARM1 with the S-adenosylmethione (SAM) mimic sinefungin and three different peptide sequences from histone H3 and PABP1 are presented, with both nonmethylated and singly methylated arginine residues exemplified. This is the first example of multiple substrate sequences solved in a single PRMT enzyme and demonstrates how the CARM1 binding site is capable of accommodating a variety of peptide sequences while maintaining a core binding mode for the unmethylated and monomethylated substrates. Comparison of these with other PRMT enzyme-peptide structures shows hydrogen bonding patterns that may be thematic of these binding sites.