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Biochem J. 2016 Oct 1;473(19):3049-63. doi: 10.1042/BCJ20160537. Epub 2016 Aug 1.

Structural basis of arginine asymmetrical dimethylation by PRMT6.

Author information

1
Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5J 1L7, Canada.
2
Chemical Biology Program, Memorial Sloan-Kettering Cancer Center, New York, N.Y 10065, U.S.A.
3
Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
4
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.
5
Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5J 1L7, Canada Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

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.

KEYWORDS:

PRMT6; arginine methyltransferase; bisubstrate inhibitor

PMID:
27480107
PMCID:
PMC5280038
DOI:
10.1042/BCJ20160537
[Indexed for MEDLINE]
Free PMC Article

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