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3JZK

crystal structure of MDM2 with chromenotriazolopyrimidine 1

Summary for 3JZK
Entry DOI10.2210/pdb3jzk/pdb
DescriptorE3 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)
Functional Keywordsmdm2, p53, inhibitor, alternative splicing, cytoplasm, host-virus interaction, ligase, metal-binding, nucleus, phosphoprotein, proto-oncogene, ubl conjugation, ubl conjugation pathway, zinc, zinc-finger
Biological sourceHomo sapiens (human)
Cellular locationNucleus, nucleoplasm: Q00987
Total number of polymer chains1
Total formula weight11692.27
Authors
Huang, X. (deposition date: 2009-09-23, release date: 2009-11-17, Last modification date: 2023-09-06)
Primary citationAllen, 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
Cited by
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
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.1 Å)
Structure validation

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