4HSG
Crystal structure of human PRMT3 in complex with an allosteric inhibitor (PRMT3- KTD)
Summary for 4HSG
| Entry DOI | 10.2210/pdb4hsg/pdb |
| Descriptor | PRMT3 protein, 1-(1,2,3-benzothiadiazol-6-yl)-3-(2-oxo-2-phenylethyl)urea, UNKNOWN ATOM OR ION, ... (4 entities in total) |
| Functional Keywords | prmt3, allosteric inhibitor, structural genomics, structural genomics consortium, sgc, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 38594.26 |
| Authors | Dobrovetsky, E.,Dong, A.,Liu, F.,Li, F.,Tempel, W.,Siarheyeva, A.,Hajian, T.,Smil, D.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Brown, P.J.,Schapira, M.,Jin, J.,Vedadi, M.,Structural Genomics Consortium (SGC) (deposition date: 2012-10-30, release date: 2012-12-05, Last modification date: 2023-09-20) |
| Primary citation | Liu, F.,Li, F.,Ma, A.,Dobrovetsky, E.,Dong, A.,Gao, C.,Korboukh, I.,Liu, J.,Smil, D.,Brown, P.J.,Frye, S.V.,Arrowsmith, C.H.,Schapira, M.,Vedadi, M.,Jin, J. Exploiting an allosteric binding site of PRMT3 yields potent and selective inhibitors. J. Med. Chem., 56:2110-2124, 2013 Cited by PubMed Abstract: Protein arginine methyltransferases (PRMTs) play an important role in diverse biological processes. Among the nine known human PRMTs, PRMT3 has been implicated in ribosomal biosynthesis via asymmetric dimethylation of the 40S ribosomal protein S2 and in cancer via interaction with the DAL-1 tumor suppressor protein. However, few selective inhibitors of PRMTs have been discovered. We recently disclosed the first selective PRMT3 inhibitor, which occupies a novel allosteric binding site and is noncompetitive with both the peptide substrate and cofactor. Here we report comprehensive structure-activity relationship studies of this series, which resulted in the discovery of multiple PRMT3 inhibitors with submicromolar potencies. An X-ray crystal structure of compound 14u in complex with PRMT3 confirmed that this inhibitor occupied the same allosteric binding site as our initial lead compound. These studies provide the first experimental evidence that potent and selective inhibitors can be created by exploiting the allosteric binding site of PRMT3. PubMed: 23445220DOI: 10.1021/jm3018332 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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