title: Structural basis of arginine asymmetrical dimethylation by PRMT6.
abstract: PRMT6 is a type I protein arginine methyltransferase, generating the asymmetric dimethylarginine mark on proteins such as histone H3R2. Asymmetric dimethylation of histone H3R2 by PRMT6 acts as a repressive mark that antagonizes trimethylation of H3 lysine 4 by the MLL histone H3K4 methyltransferase. PRMT6 is overexpressed in several cancer types, including prostate, bladder and lung cancers; therefore, it is of great interest to develop potent and selective inhibitors for PRMT6. Here, we report the synthesis of a potent bisubstrate inhibitor GMS [6'-methyleneamine sinefungin, an analog of sinefungin (SNF)], and the crystal structures of human PRMT6 in complex, respectively, with S-adenosyl-L-homocysteine (SAH) and the bisubstrate inhibitor GMS that shed light on the significantly improved inhibition effect of GMS on methylation activity of PRMT6 compared with SAH and an S-adenosyl-L-methionine competitive methyltransferase inhibitor SNF. In addition, we also crystallized PRMT6 in complex with SAH and a short arginine-containing peptide. Based on the structural information here and available in the PDB database, we proposed a mechanism that can rationalize the distinctive arginine methylation product specificity of different types of arginine methyltransferases and pinpoint the structural determinant of such a specificity.
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5J 1L7, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Chemical Biology Program, Memorial Sloan-Kettering Cancer Center, New York, N.Y 10065, U.S.A.
authors.forename: Weihong
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5J 1L7, Canada.
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Eram
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Mynol
authors.initials: M
authors.lastname: Vhuiyan
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5J 1L7, Canada.
authors.forename: Aiping
authors.initials: A
authors.lastname: Dong
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5J 1L7, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5J 1L7, Canada.
authors.forename: Hao
authors.initials: H
authors.lastname: He
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5J 1L7, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Brown
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Adam
authors.initials: A
authors.lastname: Frankel
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5J 1L7, Canada Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.affiliation: Chemical Biology Program, Memorial Sloan-Kettering Cancer Center, New York, N.Y 10065, U.S.A.
authors.forename: Minkui
authors.initials: M
authors.lastname: Luo
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5J 1L7, Canada Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Jinrong
authors.initials: J
authors.lastname: Min
mesh_terms: D000595:Amino Acid Sequence; D001120:Arginine / Q000378:metabolism*; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D006801:Humans; D008745:Methylation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D011484:Protein-Arginine N-Methyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D009687:Nuclear Proteins; D001120:Arginine; C447833:PRMT6 protein, human; D011484:Protein-Arginine N-Methyltransferases
keywords: PRMT6; arginine methyltransferase; bisubstrate inhibitor