Angewandte Chemie International Edition · 2005 · 248 citations · 22 references
Life SciencesMedicinal ChemistryMolecular BiologyMolecular OncologyProtein-protein InteractionsStructural BiologyLigand BindingProtein DegradationProtein DimerizationProtein StructureStructural DomainsHydrophobic RecognitionP53 InactivationP53-mediated SignalingTumor Suppressor P53Ubiquitin BindingUbiquitin-dependent RegulationUbiquitin-mediated DegradationUbiquitin-mediated Proteolysis
HDM2 regulates p53 by binding to its transactivation domain and promoting its ubiquitin-dependent degradation. Crystallographic analysis of the HDM2/p53 complex revealed that three hydrophobic residues (F19, W23, L26) along one face of the p53 helical peptide are essential for binding (see picture). Terphenyl-based antagonists mimic the α-helical region of p53 and disrupt HDM2/p53 complexation.
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In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Lyubomir T. Vassilev, Binh Thanh Vu, Bradford Graves et al. · Science · 2004 · 4.7K citations
Medicine, Oncology, Pharmacology +15
Mdm2 promotes the rapid degradation of p53
Ygal Haupt, Ruth Maya, Anat Kazaz et al. · Nature · 1997 · 4.5K citations
Regulation of p53 stability by Mdm2
Michael H.G. Kubbutat, Stephen N. Jones, Karen H. Vousden · Nature · 1997 · 3.3K citations
Amplification of a gene encoding a p53-associated protein in human sarcomas
Jonathan D. Oliner, Kenneth W. Kinzler, Paul S. Meltzer et al. · Nature · 1992 · 2K citations · Full text
Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53
Reiko Honda, Hirofumi Tanaka, Hideyo Yasuda · FEBS Letters · 1997 · 1.9K citations