6NT2

type 1 PRMT in complex with the inhibitor GSK3368715

6NT2 の概要

• エントリーDOI: 10.2210/pdb6nt2/pdb
• 分子名称: Protein arginine N-methyltransferase 1, S-ADENOSYL-L-HOMOCYSTEINE, N~1~-({5-[4,4-bis(ethoxymethyl)cyclohexyl]-1H-pyrazol-4-yl}methyl)-N~1~,N~2~-dimethylethane-1,2-diamine, ... (6 entities in total)
• 機能のキーワード: inhibitor, cmplex, methyl transferase, arginine, antitumor protein
• 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: 175322.42

構造登録者

Concha, N.O. (登録日: 2019-01-28, 公開日: 2019-07-10, 最終更新日: 2024-11-06)

主引用文献

Fedoriw, A.,Rajapurkar, S.R.,O'Brien, S.,Gerhart, S.V.,Mitchell, L.H.,Adams, N.D.,Rioux, N.,Lingaraj, T.,Ribich, S.A.,Pappalardi, M.B.,Shah, N.,Laraio, J.,Liu, Y.,Butticello, M.,Carpenter, C.L.,Creasy, C.,Korenchuk, S.,McCabe, M.T.,McHugh, C.F.,Nagarajan, R.,Wagner, C.,Zappacosta, F.,Annan, R.,Concha, N.O.,Thomas, R.A.,Hart, T.K.,Smith, J.J.,Copeland, R.A.,Moyer, M.P.,Campbell, J.,Stickland, K.,Mills, J.,Jacques-O'Hagan, S.,Allain, C.,Johnston, D.,Raimondi, A.,Porter Scott, M.,Waters, N.,Swinger, K.,Boriack-Sjodin, A.,Riera, T.,Shapiro, G.,Chesworth, R.,Prinjha, R.K.,Kruger, R.G.,Barbash, O.,Mohammad, H.P.
Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss.
Cancer Cell, 36:100-, 2019

PubMed Abstract: Type I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginines on proteins. Type I PRMTs and their substrates have been implicated in human cancers, suggesting inhibition of type I PRMTs may offer a therapeutic approach for oncology. The current report describes GSK3368715 (EPZ019997), a potent, reversible type I PRMT inhibitor with anti-tumor effects in human cancer models. Inhibition of PRMT5, the predominant type II PRMT, produces synergistic cancer cell growth inhibition when combined with GSK3368715. Interestingly, deletion of the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methylthioadenosine, an endogenous inhibitor of PRMT5, and correlates with sensitivity to GSK3368715 in cell lines. These data provide rationale to explore MTAP status as a biomarker strategy for patient selection.

PubMed: 31257072
DOI: 10.1016/j.ccell.2019.05.014

実験手法

X-RAY DIFFRACTION (2.48 Å)