3JZK

crystal structure of MDM2 with chromenotriazolopyrimidine 1

3JZK の概要

• エントリーDOI: 10.2210/pdb3jzk/pdb
• 分子名称: E3 ubiquitin-protein ligase Mdm2, (6R,7S)-6,7-bis(4-bromophenyl)-7,11-dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine (3 entities in total)
• 機能のキーワード: mdm2, p53, inhibitor, alternative splicing, cytoplasm, host-virus interaction, ligase, metal-binding, nucleus, phosphoprotein, proto-oncogene, ubl conjugation, ubl conjugation pathway, zinc, zinc-finger
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus, nucleoplasm: Q00987
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 11692.27

構造登録者

Huang, X. (登録日: 2009-09-23, 公開日: 2009-11-17, 最終更新日: 2023-09-06)

主引用文献

Allen, J.G.,Bourbeau, M.P.,Wohlhieter, G.E.,Bartberger, M.D.,Michelsen, K.,Hungate, R.,Gadwood, R.C.,Gaston, R.D.,Evans, B.,Mann, L.W.,Matison, M.E.,Schneider, S.,Huang, X.,Yu, D.,Andrews, P.S.,Reichelt, A.,Long, A.M.,Yakowec, P.,Yang, E.Y.,Lee, T.A.,Oliner, J.D.
Discovery and optimization of chromenotriazolopyrimidines as potent inhibitors of the mouse double minute 2-tumor protein 53 protein-protein interaction.
J.Med.Chem., 52:7044-7053, 2009

PubMed Abstract: Tumor protein 53 (p53) is a critical regulator of cell cycle and apoptosis that is frequently disabled in human tumors. In many tumor types, p53 is deleted or mutated, but in others p53 is inactivated by overexpression or amplification of its negative regulator mouse double minute 2 (MDM2). A high-throughput screening effort identified 6,7-bis(4-bromophenyl)-7,12-dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine as a potent inhibitor of the MDM2-p53 protein-protein interaction. This screening hit was found to be chemically unstable and difficult to handle due to poor DMSO solubility. Co-crystallization with the target protein helped to direct further optimization and provided a tractable lead series of novel MDM2-p53 inhibitors. In cellular assays, these compounds were shown to upregulate p53 protein levels and p53 signaling and to cause p53-dependent inhibition of proliferation and apoptosis.

PubMed: 19856920
DOI: 10.1021/jm900681h

実験手法

X-RAY DIFFRACTION (2.1 Å)