4X60

Crystal structure of PRMT5:MEP50 with EPZ015666 and sinefungin

4X60 の概要

• エントリーDOI: 10.2210/pdb4x60/pdb
• 関連するPDBエントリー: 4X61 4X63
• 分子名称: Protein arginine N-methyltransferase 5, Methylosome protein 50, SINEFUNGIN, ... (6 entities in total)
• 機能のキーワード: protein-inhibitor complex, protein arginine methyltransferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Cytoplasm: O14744; Nucleus: Q9BQA1
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 112667.14

構造登録者

Boriack-Sjodin, P.A. (登録日: 2014-12-06, 公開日: 2015-04-22, 最終更新日: 2024-02-28)

主引用文献

Chan-Penebre, E.,Kuplast, K.G.,Majer, C.R.,Boriack-Sjodin, P.A.,Wigle, T.J.,Johnston, L.D.,Rioux, N.,Munchhof, M.J.,Jin, L.,Jacques, S.L.,West, K.A.,Lingaraj, T.,Stickland, K.,Ribich, S.A.,Raimondi, A.,Scott, M.P.,Waters, N.J.,Pollock, R.M.,Smith, J.J.,Barbash, O.,Pappalardi, M.,Ho, T.F.,Nurse, K.,Oza, K.P.,Gallagher, K.T.,Kruger, R.,Moyer, M.P.,Copeland, R.A.,Chesworth, R.,Duncan, K.W.
A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models.
Nat.Chem.Biol., 11:432-437, 2015

PubMed Abstract: Protein arginine methyltransferase-5 (PRMT5) is reported to have a role in diverse cellular processes, including tumorigenesis, and its overexpression is observed in cell lines and primary patient samples derived from lymphomas, particularly mantle cell lymphoma (MCL). Here we describe the identification and characterization of a potent and selective inhibitor of PRMT5 with antiproliferative effects in both in vitro and in vivo models of MCL. EPZ015666 (GSK3235025) is an orally available inhibitor of PRMT5 enzymatic activity in biochemical assays with a half-maximal inhibitory concentration (IC50) of 22 nM and broad selectivity against a panel of other histone methyltransferases. Treatment of MCL cell lines with EPZ015666 led to inhibition of SmD3 methylation and cell death, with IC50 values in the nanomolar range. Oral dosing with EPZ015666 demonstrated dose-dependent antitumor activity in multiple MCL xenograft models. EPZ015666 represents a validated chemical probe for further study of PRMT5 biology and arginine methylation in cancer and other diseases.

PubMed: 25915199
DOI: 10.1038/nchembio.1810

実験手法

X-RAY DIFFRACTION (2.35 Å)