4QQN

Protein arginine methyltransferase 3 in complex with compound MTV044246

4QQN の概要

• エントリーDOI: 10.2210/pdb4qqn/pdb
• 分子名称: PRMT3 protein, 1-{2-[1-(aminomethyl)cyclohexyl]ethyl}-3-isoquinolin-6-ylurea, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: prmt3, structural genomics, structural genomics consortium, sgc, transferase, epigenetics
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38735.90

構造登録者

Dong, A.,Dobrovetsky, E.,Tempel, W.,He, H.,Zhao, K.,Smil, D.,Landon, M.,Luo, X.,Chen, Z.,Dai, M.,Yu, Z.,Lin, Y.,Zhang, H.,Zhao, K.,Schapira, M.,Brown, P.J.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Vedadi, M.,Structural Genomics Consortium (SGC) (登録日: 2014-06-27, 公開日: 2014-09-17, 最終更新日: 2023-09-20)

主引用文献

Kaniskan, H.U.,Eram, M.S.,Zhao, K.,Szewczyk, M.M.,Yang, X.,Schmidt, K.,Luo, X.,Xiao, S.,Dai, M.,He, F.,Zang, I.,Lin, Y.,Li, F.,Dobrovetsky, E.,Smil, D.,Min, S.J.,Lin-Jones, J.,Schapira, M.,Atadja, P.,Li, E.,Barsyte-Lovejoy, D.,Arrowsmith, C.H.,Brown, P.J.,Liu, F.,Yu, Z.,Vedadi, M.,Jin, J.
Discovery of Potent and Selective Allosteric Inhibitors of Protein Arginine Methyltransferase 3 (PRMT3).
J. Med. Chem., 61:1204-1217, 2018

PubMed Abstract: PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is crucial for maturation of ribosomes and has been implicated in several diseases. We recently disclosed a highly potent, selective, and cell-active allosteric inhibitor of PRMT3, compound 4. Here, we report comprehensive structure-activity relationship studies that target the allosteric binding site of PRMT3. We conducted design, synthesis, and evaluation of novel compounds in biochemical, selectivity, and cellular assays that culminated in the discovery of 4 and other highly potent (IC values: ∼10-36 nM), selective, and cell-active allosteric inhibitors of PRMT3 (compounds 29, 30, 36, and 37). In addition, we generated compounds that are very close analogs of these potent inhibitors but displayed drastically reduced potency as negative controls (compounds 49-51). These inhibitors and negative controls are valuable chemical tools for the biomedical community to further investigate biological functions and disease associations of PRMT3.

PubMed: 29244490
DOI: 10.1021/acs.jmedchem.7b01674

実験手法

X-RAY DIFFRACTION (2.08 Å)