title: Structural Insights into Ternary Complex Formation of Human CARM1 with Various Substrates.
abstract: 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.
authors.affiliation: Epizyme, Inc. 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: P Ann
authors.initials: PA
authors.lastname: Boriack-Sjodin
authors.affiliation: Epizyme, Inc. 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.affiliation: Epizyme, Inc. 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Jacques
authors.affiliation: Epizyme, Inc. 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Allison
authors.initials: A
authors.lastname: Drew
authors.affiliation: Epizyme, Inc. 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: Sneeringer
authors.affiliation: Epizyme, Inc. 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Margaret Porter
authors.initials: MP
authors.lastname: Scott
authors.affiliation: Epizyme, Inc. 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Mikel P
authors.initials: MP
authors.lastname: Moyer
authors.affiliation: Epizyme, Inc. 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Ribich
authors.affiliation: Epizyme, Inc. 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Oscar
authors.initials: O
authors.lastname: Moradei
authors.affiliation: Epizyme, Inc. 400 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D011484:Protein-Arginine N-Methyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1