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An allosteric inhibitor of protein arginine methyltransferase 3.
- Source :
-
Structure (London, England : 1993) [Structure] 2012 Aug 08; Vol. 20 (8), pp. 1425-35. Date of Electronic Publication: 2012 Jul 12. - Publication Year :
- 2012
-
Abstract
- 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 IC50 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.<br /> (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Subjects :
- Allosteric Regulation
Allosteric Site
Amino Acid Substitution
Caco-2 Cells
Catalytic Domain
Cell Membrane Permeability
Crystallography, X-Ray
Enzyme Inhibitors metabolism
Humans
Hydrogen Bonding
Kinetics
Microsomes, Liver drug effects
Microsomes, Liver metabolism
Models, Molecular
Mutagenesis, Site-Directed
Protein Binding
Protein Structure, Secondary
Protein-Arginine N-Methyltransferases genetics
Structure-Activity Relationship
Thiadiazoles metabolism
Urea chemistry
Urea metabolism
Enzyme Inhibitors chemistry
Protein-Arginine N-Methyltransferases antagonists & inhibitors
Protein-Arginine N-Methyltransferases chemistry
Thiadiazoles chemistry
Urea analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1878-4186
- Volume :
- 20
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Structure (London, England : 1993)
- Publication Type :
- Academic Journal
- Accession number :
- 22795084
- Full Text :
- https://doi.org/10.1016/j.str.2012.06.001