7PPY

CARM1 in complex with EML709

7PPY の概要

• エントリーDOI: 10.2210/pdb7ppy/pdb
• 分子名称: Histone-arginine methyltransferase CARM1, methyl 6-[4-[[~{N}-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl]carbamimidoyl]amino]butylcarbamoylamino]-4-oxidanyl-naphthalene-2-carboxylate, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: protein arginine n-methyltransferase, prmt4, carm1, inhibitor, transcription
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 166637.17

構造登録者

Marechal, N.,Cura, V.,Bonnefond, L.,Troffer-Charlier, N.,Cavarelli, J. (登録日: 2021-09-15, 公開日: 2022-04-06, 最終更新日: 2024-01-31)

主引用文献

Iannelli, G.,Milite, C.,Marechal, N.,Cura, V.,Bonnefond, L.,Troffer-Charlier, N.,Feoli, A.,Rescigno, D.,Wang, Y.,Cipriano, A.,Viviano, M.,Bedford, M.T.,Cavarelli, J.,Castellano, S.,Sbardella, G.
Turning Nonselective Inhibitors of Type I Protein Arginine Methyltransferases into Potent and Selective Inhibitors of Protein Arginine Methyltransferase 4 through a Deconstruction-Reconstruction and Fragment-Growing Approach.
J.Med.Chem., 65:11574-11606, 2022

PubMed Abstract: Protein arginine methyltransferases (PRMTs) are important therapeutic targets, playing a crucial role in the regulation of many cellular processes and being linked to many diseases. Yet, there is still much to be understood regarding their functions and the biological pathways in which they are involved, as well as on the structural requirements that could drive the development of selective modulators of PRMT activity. Here we report a deconstruction-reconstruction approach that, starting from a series of type I PRMT inhibitors previously identified by us, allowed for the identification of potent and selective inhibitors of PRMT4, which regardless of the low cell permeability show an evident reduction of arginine methylation levels in MCF7 cells and a marked reduction of proliferation. We also report crystal structures with various PRMTs supporting the observed specificity and selectivity.

PubMed: 35482954
DOI: 10.1021/acs.jmedchem.2c00252

実験手法

X-RAY DIFFRACTION (2.42 Å)