6V0P

PRMT5 complex bound to covalent PBM inhibitor BRD6711

6V0P の概要

• エントリーDOI: 10.2210/pdb6v0p/pdb
• 分子名称: Protein arginine N-methyltransferase 5, Methylosome protein 50, 2-(5-chloro-6-oxopyridazin-1(6H)-yl)-N-(4-methyl-3-sulfamoylphenyl)acetamide, ... (7 entities in total)
• 機能のキーワード: methyltransferase, splicing, sdma, epigenetic, splicing-transferase complex, splicing/transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 110483.09

構造登録者

McMillan, B.J.,McKinney, D.C. (登録日: 2019-11-19, 公開日: 2020-11-25, 最終更新日: 2024-10-23)

主引用文献

McKinney, D.C.,McMillan, B.J.,Ranaghan, M.J.,Moroco, J.A.,Brousseau, M.,Mullin-Bernstein, Z.,O'Keefe, M.,McCarren, P.,Mesleh, M.F.,Mulvaney, K.M.,Robinson, F.,Singh, R.,Bajrami, B.,Wagner, F.F.,Hilgraf, R.,Drysdale, M.J.,Campbell, A.J.,Skepner, A.,Timm, D.E.,Porter, D.,Kaushik, V.K.,Sellers, W.R.,Ianari, A.
Discovery of a First-in-Class Inhibitor of the PRMT5-Substrate Adaptor Interaction.
J.Med.Chem., 64:11148-11168, 2021

PubMed Abstract: PRMT5 and its substrate adaptor proteins (SAPs), pICln and Riok1, are synthetic lethal dependencies in MTAP-deleted cancer cells. SAPs share a conserved PRMT5 binding motif (PBM) which mediates binding to a surface of PRMT5 distal to the catalytic site. This interaction is required for methylation of several PRMT5 substrates, including histone and spliceosome complexes. We screened for small molecule inhibitors of the PRMT5-PBM interaction and validated a compound series which binds to the PRMT5-PBM interface and directly inhibits binding of SAPs. Mode of action studies revealed the formation of a covalent bond between a halogenated pyridazinone group and cysteine 278 of PRMT5. Optimization of the starting hit produced a lead compound, BRD0639, which engages the target in cells, disrupts PRMT5-RIOK1 complexes, and reduces substrate methylation. BRD0639 is a first-in-class PBM-competitive inhibitor that can support studies of PBM-dependent PRMT5 activities and the development of novel PRMT5 inhibitors that selectively target these functions.

PubMed: 34342224
DOI: 10.1021/acs.jmedchem.1c00507

実験手法

X-RAY DIFFRACTION (1.88 Å)