8G2G

Crystal structure of PRMT3 with compound YD1113

Summary for 8G2G

• Entry DOI: 10.2210/pdb8g2g/pdb
• Descriptor: Protein arginine N-methyltransferase 3, 5'-S-[2-(benzylcarbamamido)ethyl]-5'-thioadenosine, SULFATE ION, ... (4 entities in total)
• Functional Keywords: prmt3, yd1113, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 77675.00

Authors

Song, X.,Dong, A.,Arrowsmith, C.H.,Edwards, A.M.,Deng, Y.,Huang, R.,Min, J. (deposition date: 2023-02-03, release date: 2023-04-26, Last modification date: 2024-02-21)

Primary citation

Deng, Y.,Song, X.,Iyamu, I.D.,Dong, A.,Min, J.,Huang, R.
A unique binding pocket induced by a noncanonical SAH mimic to develop potent and selective PRMT inhibitors.
Acta Pharm Sin B, 13:4893-4905, 2023

PubMed Abstract: Protein arginine methyltransferases (PRMTs) are attractive targets for developing therapeutic agents, but selective PRMT inhibitors targeting the cofactor SAM binding site are limited. Herein, we report the discovery of a noncanonical but less polar SAH surrogate YD1113 by replacing the benzyl guanidine of a pan-PRMT inhibitor with a benzyl urea, potently and selectively inhibiting PRMT3/4/5. Importantly, crystal structures reveal that the benzyl urea moiety of YD1113 induces a unique and novel hydrophobic binding pocket in PRMT3/4, providing a structural basis for the selectivity. In addition, YD1113 can be modified by introducing a substrate mimic to form a "T-shaped" bisubstrate analogue YD1290 to engage both the SAM and substrate binding pockets, exhibiting potent and selective inhibition to type I PRMTs (IC < 5 nmol/L). In summary, we demonstrated the promise of YD1113 as a general SAH mimic to build potent and selective PRMT inhibitors.

PubMed: 38045046
DOI: 10.1016/j.apsb.2023.07.022

Experimental method

X-RAY DIFFRACTION (2.02 Å)