2Y1W

CRYSTAL STRUCTURE OF COACTIVATOR ASSOCIATED ARGININE METHYLTRANSFERASE 1 (CARM1) IN COMPLEX WITH SINEFUNGIN AND INDOLE INHIBITOR

2Y1W の概要

• エントリーDOI: 10.2210/pdb2y1w/pdb
• 関連するPDBエントリー: 2Y1X
• 分子名称: HISTONE-ARGININE METHYLTRANSFERASE CARM1, SINEFUNGIN, 2-{4-[3-FLUORO-2-(2-METHOXYPHENYL)-1H-INDOL-5-YL] PIPERIDIN-1-YL}-N-METHYLETHANAMINE, ... (4 entities in total)
• 機能のキーワード: histone modification, transferase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Nucleus: Q86X55
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 160971.13

構造登録者

Sack, J.S.,Thieffine, S.,Bandiera, T.,Fasolini, M.,Duke, G.J.,Jayaraman, L.,Kish, K.F.,Klei, H.E.,Purandare, A.V.,Rosettani, P.,Troiani, S.,Xie, D.,Bertrand, J.A. (登録日: 2010-12-10, 公開日: 2011-03-23, 最終更新日: 2024-05-08)

主引用文献

Sack, J.S.,Thieffine, S.,Bandiera, T.,Fasolini, M.,Duke, G.J.,Jayaraman, L.,Kish, K.F.,Klei, H.E.,Purandare, A.V.,Rosettani, P.,Troiani, S.,Xie, D.,Bertrand, J.A.
Structural Basis for Carm1 Inhibition by Indole and Pyrazole Inhibitors
Biochem.J., 436:331-, 2011

PubMed Abstract: CARM1 (co-activator-associated arginine methyltransferase 1) is a PRMT (protein arginine N-methyltransferase) family member that catalyses the transfer of methyl groups from SAM (S-adenosylmethionine) to the side chain of specific arginine residues of substrate proteins. This post-translational modification of proteins regulates a variety of transcriptional events and other cellular processes. Moreover, CARM1 is a potential oncological target due to its multiple roles in transcription activation by nuclear hormone receptors and other transcription factors such as p53. Here, we present crystal structures of the CARM1 catalytic domain in complex with cofactors [SAH (S-adenosyl-L-homocysteine) or SNF (sinefungin)] and indole or pyazole inhibitors. Analysis of the structures reveals that the inhibitors bind in the arginine-binding cavity and the surrounding pocket that exists at the interface between the N- and C-terminal domains. In addition, we show using ITC (isothermal titration calorimetry) that the inhibitors bind to the CARM1 catalytic domain only in the presence of the cofactor SAH. Furthermore, sequence differences for select residues that interact with the inhibitors may be responsible for the CARM1 selectivity against PRMT1 and PRMT3. Together, the structural and biophysical information should aid in the design of both potent and specific inhibitors of CARM1.

PubMed: 21410432
DOI: 10.1042/BJ20102161

実験手法

X-RAY DIFFRACTION (2.1 Å)