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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