8UQH

X-ray crystal structure of PRMT4 bound to compound YD-1130

Summary for 8UQH

• Entry DOI: 10.2210/pdb8uqh/pdb
• Descriptor: Histone-arginine methyltransferase CARM1, 5'-S-(2-{[(3-bromophenyl)methyl]amino}ethyl)-5'-thioadenosine (3 entities in total)
• Functional Keywords: transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 157078.21

Authors

Bush, M.,Noinaj, N.,Deng, Y.,Huang, R. (deposition date: 2023-10-23, release date: 2025-04-02)

Primary citation

Deng, Y.,Kim, E.J.,Song, X.,Kulkarni, A.S.,Zhu, R.X.,Wang, Y.,Bush, M.,Dong, A.,Noinaj, N.,Min, J.,Xu, W.,Huang, R.
An Adenosine Analogue Library Reveals Insights into Active Sites of Protein Arginine Methyltransferases and Enables the Discovery of a Selective PRMT4 Inhibitor.
J.Med.Chem., 67:18053-18069, 2024

PubMed Abstract: Protein arginine methyltransferases (PRMTs) represent promising drug targets. However, the lack of isoform-selective chemical probes poses a significant hurdle in deciphering their biological roles. To address this issue, we devised a library of 100 diverse adenosine analogues, enabling a detailed exploration of the active site of PRMTs. Despite their close homology, our analysis unveiled specific chemical trends unique to the individual members. Notably, compound YD1130 demonstrated over 1000-fold selectivity for PRMT4 (IC < 0.5 nM) over a panel of 38 methyltransferases, including the other PRMTs. Its prodrug YD1342 exhibited potent inhibition on cellular substrate methylation, breast cancer cell colony formation, and tumor growth in the animal model, surpassing or matching known PRMT4-specific inhibitors. In summary, our focused library not only illuminates the intricate active sites of PRMTs to facilitate the discovery of highly potent and isoform-selective probes but also offers a versatile blueprint for identifying chemical probes for other methyltransferases.

PubMed: 39361813
DOI: 10.1021/acs.jmedchem.4c01041

Experimental method

X-RAY DIFFRACTION (1.87 Å)