6W6D

Crystal Structure of Human Protein arginine N-methyltransferase 6 (PRMT6) in complex with SGC6870 inhibitor

Summary for 6W6D

• Entry DOI: 10.2210/pdb6w6d/pdb
• Descriptor: Protein arginine N-methyltransferase 6, S-ADENOSYL-L-HOMOCYSTEINE, (5R)-4-(5-bromothiophene-2-carbonyl)-5-(3,5-dimethylphenyl)-7-methyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one, ... (4 entities in total)
• Functional Keywords: prmt6 and sgc6870 inhibitor, structural genomics, structural genomics consortium, sgc, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 42928.36

Authors

Halabelian, L.,Zeng, H.,Dong, A.,Jin, J.,Shen, Y.,Kaniskan, H.U.,Hutchinson, A.,Seitova, A.,Bountra, C.,Edwards, A.M.,Arrowsmith, C.H.,Brown, P.J.,Structural Genomics Consortium (SGC) (deposition date: 2020-03-16, release date: 2020-04-29, Last modification date: 2024-10-16)

Primary citation

Shen, Y.,Li, F.,Szewczyk, M.M.,Halabelian, L.,Chau, I.,Eram, M.S.,Dela Sena, C.,Park, K.S.,Meng, F.,Chen, H.,Zeng, H.,Dong, A.,Wu, H.,Trush, V.V.,McLeod, D.,Zepeda-Velazquez, C.A.,Campbell, R.M.,Mader, M.M.,Watson, B.M.,Schapira, M.,Arrowsmith, C.H.,Al-Awar, R.,Barsyte-Lovejoy, D.,Kaniskan, H.U.,Brown, P.J.,Vedadi, M.,Jin, J.
A First-in-Class, Highly Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 6.
J.Med.Chem., 64:3697-3706, 2021

PubMed Abstract: Protein arginine methyltransferase 6 (PRMT6) catalyzes monomethylation and asymmetric dimethylation of arginine residues in various proteins, plays important roles in biological processes, and is associated with multiple cancers. To date, a highly selective PRMT6 inhibitor has not been reported. Here we report the discovery and characterization of a first-in-class, highly selective allosteric inhibitor of PRMT6, (SGC6870). is a potent PRMT6 inhibitor (IC = 77 ± 6 nM) with outstanding selectivity for PRMT6 over a broad panel of other methyltransferases and nonepigenetic targets. Notably, the crystal structure of the PRMT6- complex and kinetic studies revealed binds a unique, induced allosteric pocket. Additionally, engages PRMT6 and potently inhibits its methyltransferase activity in cells. Moreover, 's enantiomer, (SGC6870N), is inactive against PRMT6 and can be utilized as a negative control. Collectively, - is a well-characterized PRMT6 chemical probe and a valuable tool for further investigating PRMT6 functions in health and disease.

PubMed: 33591753
DOI: 10.1021/acs.jmedchem.0c02160

Experimental method

X-RAY DIFFRACTION (1.91 Å)