Structural basis of arginine asymmetrical dimethylation by PRMT6 Journal Article


Authors: Wu, H.; Zheng, W.; Eram, M. S.; Vhuiyan, M.; Dong, A.; Zeng, H.; He, H.; Brown, P.; Frankel, A.; Vedadi, M.; Luo, M.; Min, J.
Article 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 [60-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. ©2016 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.
Journal Title: Biochemical Journal
Volume: 473
Issue: 19
ISSN: 0264-6021
Publisher: Portland Press Ltd  
Date Published: 2016-10-01
Start Page: 3049
End Page: 3063
Language: English
DOI: 10.1042/bcj20160537
PROVIDER: scopus
PMCID: PMC5280038
PUBMED: 27480107
DOI/URL:
Notes: Article -- Export Date: 2 February 2017 -- Source: Scopus
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MSK Authors
  1. Weihong Zheng
    11 Zheng
  2. Minkui Luo
    65 Luo