6K1S

Discovery of Potent and Selective Covalent Protein Arginine Methyltransferase (PRMT5) Inhibitors

Summary for 6K1S

• Entry DOI: 10.2210/pdb6k1s/pdb
• Descriptor: Protein arginine N-methyltransferase 5, Methylosome protein 50, 2-[[7-[(2~{R},3~{R},4~{S},5~{R})-5-[(~{R})-(4-chlorophenyl)-oxidanyl-methyl]-3,4-bis(oxidanyl)oxolan-2-yl]pyrrolo[2,3-d]pyrimidin-4-yl]amino]ethanal, ... (6 entities in total)
• Functional Keywords: prmt5, complex, covalent, inhibitor, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 112557.47

Authors

Tong, S.,Lin, H. (deposition date: 2019-05-12, release date: 2019-06-19, Last modification date: 2024-11-06)

Primary citation

Lin, H.,Wang, M.,Zhang, Y.W.,Tong, S.,Leal, R.A.,Shetty, R.,Vaddi, K.,Luengo, J.I.
Discovery of Potent and Selective Covalent Protein Arginine Methyltransferase 5 (PRMT5) Inhibitors.
Acs Med.Chem.Lett., 10:1033-1038, 2019

PubMed Abstract: Protein arginine methyltransferase 5 (PRMT5) is known to symmetrically dimethylate numerous cytosolic and nuclear proteins that are involved in a variety of cellular processes. Recent findings have revealed its potential as a cancer therapeutic target. PRMT5 possesses a cysteine (C449) in the active site, unique to PRMT5. Therefore, covalent PRMT5 inhibition is an attractive chemical approach. Herein, we report an exciting discovery of a series of novel hemiaminals that under physiological conditions can be converted to aldehydes and react with C449 to form covalent adducts, which presumably undergo an unprecedented elimination to form the thiol-vinyl ethers, as indicated by electron density in the co-crystal structure of the PRMT5/MEP50 complex.

PubMed: 31312404
DOI: 10.1021/acsmedchemlett.9b00074

Experimental method

X-RAY DIFFRACTION (2.6 Å)