4RYL

Human Protein Arginine Methyltransferase 3 in complex with 1-isoquinolin-6-yl-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]urea

Summary for 4RYL

• Entry DOI: 10.2210/pdb4ryl/pdb
• Descriptor: PRMT3 protein, 1-isoquinolin-6-yl-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]urea, UNKNOWN ATOM OR ION, ... (4 entities in total)
• Functional Keywords: prmt3, sgc707, structural genomics, structural genomics consortium, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 38580.25

Authors

Dong, A.,Dobrovetsky, E.,Kaniskan, H.U.,Szewczyk, M.,Yu, Z.,Eram, M.S.,Yang, X.,Schmidt, K.,Luo, X.,Dai, M.,He, F.,Zang, I.,Lin, Y.,Kennedy, S.,Li, F.,Tempel, W.,Smil, D.,Min, S.J.,Landon, M.,Lin-Jones, J.,Huang, X.P.,Roth, B.L.,Schapira, M.,Atadja, P.,Barsyte-Lovejoy, D.,Bountra, C.,Edwards, A.M.,Arrowsmith, C.H.,Brown, P.J.,Zhao, K.,Jin, J.,Vedadi, M.,Structural Genomics Consortium (SGC) (deposition date: 2014-12-15, release date: 2015-02-25, Last modification date: 2023-09-20)

Primary citation

Kaniskan, H.U.,Szewczyk, M.M.,Yu, Z.,Eram, M.S.,Yang, X.,Schmidt, K.,Luo, X.,Dai, M.,He, F.,Zang, I.,Lin, Y.,Kennedy, S.,Li, F.,Dobrovetsky, E.,Dong, A.,Smil, D.,Min, S.J.,Landon, M.,Lin-Jones, J.,Huang, X.P.,Roth, B.L.,Schapira, M.,Atadja, P.,Barsyte-Lovejoy, D.,Arrowsmith, C.H.,Brown, P.J.,Zhao, K.,Jin, J.,Vedadi, M.
A Potent, Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3).
Angew.Chem.Int.Ed.Engl., 54:5166-5170, 2015

PubMed Abstract: PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is essential for maturation of ribosomes, may have a role in lipogenesis, and is implicated in several diseases. A potent, selective, and cell-active PRMT3 inhibitor would be a valuable tool for further investigating PRMT3 biology. Here we report the discovery of the first PRMT3 chemical probe, SGC707, by structure-based optimization of the allosteric PRMT3 inhibitors we reported previously, and thorough characterization of this probe in biochemical, biophysical, and cellular assays. SGC707 is a potent PRMT3 inhibitor (IC50 =31±2 nM, KD =53±2 nM) with outstanding selectivity (selective against 31 other methyltransferases and more than 250 non-epigenetic targets). The mechanism of action studies and crystal structure of the PRMT3-SGC707 complex confirm the allosteric inhibition mode. Importantly, SGC707 engages PRMT3 and potently inhibits its methyltransferase activity in cells. It is also bioavailable and suitable for animal studies. This well-characterized chemical probe is an excellent tool to further study the role of PRMT3 in health and disease.

PubMed: 25728001
DOI: 10.1002/anie.201412154

Experimental method

X-RAY DIFFRACTION (2.1 Å)