6S71

Crystal structure of CARM1 in complex with inhibitor WH5C

6S71 の概要

• エントリーDOI: 10.2210/pdb6s71/pdb
• 分子名称: Histone-arginine methyltransferase CARM1, (2~{S})-4-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl-(5-carbamimidamidopentyl)amino]-2-azanyl-butanoic acid, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: inhibitor, complex, arginine methyltransferase, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 162716.79

構造登録者

Gunnell, E.A.,Muhsen, U.,Dowden, J.,Dreveny, I. (登録日: 2019-07-04, 公開日: 2020-03-04, 最終更新日: 2024-05-15)

主引用文献

Gunnell, E.A.,Al-Noori, A.,Muhsen, U.,Davies, C.C.,Dowden, J.,Dreveny, I.
Structural and biochemical evaluation of bisubstrate inhibitors of protein arginine N-methyltransferases PRMT1 and CARM1 (PRMT4).
Biochem.J., 477:787-800, 2020

PubMed Abstract: Attenuating the function of protein arginine methyltransferases (PRMTs) is an objective for the investigation and treatment of several diseases including cardiovascular disease and cancer. Bisubstrate inhibitors that simultaneously target binding sites for arginine substrate and the cofactor (S-adenosylmethionine (SAM)) have potential utility, but structural information on their binding is required for their development. Evaluation of bisubstrate inhibitors featuring an isosteric guanidine replacement with two prominent enzymes PRMT1 and CARM1 (PRMT4) by isothermal titration calorimetry (ITC), activity assays and crystallography are reported. Key findings are that 2-aminopyridine is a viable replacement for guanidine, providing an inhibitor that binds more strongly to CARM1 than PRMT1. Moreover, a residue around the active site that differs between CARM1 (Asn-265) and PRMT1 (Tyr-160) is identified that affects the side chain conformation of the catalytically important neighbouring glutamate in the crystal structures. Mutagenesis data supports its contribution to the difference in binding observed for this inhibitor. Structures of CARM1 in complex with a range of seven inhibitors reveal the binding modes and show that inhibitors with an amino acid terminus adopt a single conformation whereas the electron density for equivalent amine-bearing inhibitors is consistent with preferential binding in two conformations. These findings inform the molecular basis of CARM1 ligand binding and identify differences between CARM1 and PRMT1 that can inform drug discovery efforts.

PubMed: 32011657
DOI: 10.1042/BCJ20190826

実験手法

X-RAY DIFFRACTION (2.062 Å)