5EGS

Human PRMT6 with bound fragment-type inhibitor

Summary for 5EGS

• Entry DOI: 10.2210/pdb5egs/pdb
• Related: 4QPP
• Descriptor: Protein arginine N-methyltransferase 6, S-ADENOSYL-L-HOMOCYSTEINE, 2-[4-(phenylmethyl)piperidin-1-yl]ethanamine, ... (4 entities in total)
• Functional Keywords: fragment, inhibitor, prmt, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : Q96LA8
• Total number of polymer chains: 4
• Total formula weight: 171145.91

Authors

Steuber, H.,Egner, U.,Kania, J.,Wu, H.,Brown, P.J. (deposition date: 2015-10-27, release date: 2016-02-03, Last modification date: 2024-01-10)

Primary citation

Ferreira de Freitas, R.,Eram, M.S.,Szewczyk, M.M.,Steuber, H.,Smil, D.,Wu, H.,Li, F.,Senisterra, G.,Dong, A.,Brown, P.J.,Hitchcock, M.,Moosmayer, D.,Stegmann, C.M.,Egner, U.,Arrowsmith, C.,Barsyte-Lovejoy, D.,Vedadi, M.,Schapira, M.
Discovery of a Potent Class I Protein Arginine Methyltransferase Fragment Inhibitor.
J.Med.Chem., 59:1176-1183, 2016

PubMed Abstract: Protein methyltransferases (PMTs) are a promising target class in oncology and other disease areas. They are composed of SET domain methyltransferases and structurally unrelated Rossman-fold enzymes that include protein arginine methyltransferases (PRMTs). In the absence of a well-defined medicinal chemistry tool-kit focused on PMTs, most current inhibitors were identified by screening large and diverse libraries of leadlike molecules. So far, no successful fragment-based approach was reported against this target class. Here, by deconstructing potent PRMT inhibitors, we find that chemical moieties occupying the substrate arginine-binding site can act as efficient fragment inhibitors. Screening a fragment library against PRMT6 produced numerous hits, including a 300 nM inhibitor (ligand efficiency of 0.56) that decreased global histone 3 arginine 2 methylation in cells, and can serve as a warhead for the development of PRMT chemical probes.

PubMed: 26824386
DOI: 10.1021/acs.jmedchem.5b01772

Experimental method

X-RAY DIFFRACTION (2.15 Å)