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An Allosteric Inhibitor of Protein Arginine Methyltransferase 3.
MedLine Citation:
PMID:  22795084     Owner:  NLM     Status:  Publisher    
PRMT3, a protein arginine methyltransferase, has been shown to influence ribosomal biosynthesis by catalyzing the dimethylation of the 40S ribosomal protein S2. Although PRMT3 has been reported to be a cytosolic protein, it has been shown to methylate histone H4 peptide (H4 1-24) in vitro. Here, we report the identification of a PRMT3 inhibitor (1-(benzo[d][1,2,3]thiadiazol-6-yl)-3-(2-cyclohexenylethyl)urea; compound 1) with IC(50) value of 2.5 μM by screening a library of 16,000 compounds using H4 (1-24) peptide as a substrate. The crystal structure of PRMT3 in complex with compound 1 as well as kinetic analysis reveals an allosteric mechanism of inhibition. Mutating PRMT3 residues within the allosteric site or using compound 1 analogs that disrupt interactions with allosteric site residues both abrogated binding and inhibitory activity. These data demonstrate an allosteric mechanism for inhibition of protein arginine methyltransferases, an emerging class of therapeutic targets.
Alena Siarheyeva; Guillermo Senisterra; Abdellah Allali-Hassani; Aiping Dong; Elena Dobrovetsky; Gregory A Wasney; Irene Chau; Richard Marcellus; Taraneh Hajian; Feng Liu; Ilia Korboukh; David Smil; Yuri Bolshan; Jinrong Min; Hong Wu; Hong Zeng; Peter Loppnau; Gennadiy Poda; Carly Griffin; Ahmed Aman; Peter J Brown; Jian Jin; Rima Al-Awar; Cheryl H Arrowsmith; Matthieu Schapira; Masoud Vedadi
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-7-10
Journal Detail:
Title:  Structure (London, England : 1993)     Volume:  -     ISSN:  1878-4186     ISO Abbreviation:  -     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-7-16     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101087697     Medline TA:  Structure     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
Structural Genomics Consortium, University of Toronto, 101 College Street, MaRS Centre, South Tower, Toronto, ON M5G 1L7, Canada.
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