Journal
BIOCHEMICAL JOURNAL
Volume 473, Issue -, Pages 3049-3063Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BCJ20160537
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Funding
- National Institute of General Medical Science [R01GM096056]
- NCI Cancer Center Support Grant [P30 CA08748]
- Starr Cancer Consortium
- Mr William H. Goodwin and Mrs Alice Goodwin
- Commonwealth Foundation for Cancer Research
- Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center
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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.
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