2axi
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(New page: 200px<br /> <applet load="2axi" size="450" color="white" frame="true" align="right" spinBox="true" caption="2axi, resolution 1.40Å" /> '''HDM2 in complex wit...)
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Revision as of 18:49, 12 November 2007
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HDM2 in complex with a beta-hairpin
Overview
Inhibitors of the interaction between the p53 tumor-suppressor protein and, its natural human inhibitor HDM2 are attractive as potential anticancer, agents. In earlier work we explored designing beta-hairpin peptidomimetics, of the alpha-helical epitope on p53 that would bind tightly to the, p53-binding site on HDM2. The beta-hairpin is used as a scaffold to, display energetically hot residues in an optimal array for interaction, with HDM2. The initial lead beta-hairpin mimetic, with a weak inhibitory, activity (IC(50)=125 microM), was optimized to afford, cyclo-(L-Pro-Phe-Glu-6ClTrp-Leu-Asp-Trp-Glu-Phe-D-Pro) (where, 6ClTrp=L-6-chlorotryptophan), which has an affinity almost 1,000 times, higher (IC(50)=140 nM). In this work, insights into the origins of this, affinity maturation based on structure-activity studies and an X-ray, crystal structure of the inhibitor/HDM2(residues 17-125) complex at 1.4 A, resolution are described. The crystal structure confirms the beta-hairpin, conformation of the bound ligand, and also reveals that a significant, component of the affinity increase arises through new aromatic/aromatic, stacking interactions between side chains around the hairpin and groups on, the surface of HDM2.
About this Structure
2AXI is a Single protein structure of sequence from Homo sapiens with SO4 and MPO as ligands. Full crystallographic information is available from OCA.
Reference
Structure-activity studies in a family of beta-hairpin protein epitope mimetic inhibitors of the p53-HDM2 protein-protein interaction., Fasan R, Dias RL, Moehle K, Zerbe O, Obrecht D, Mittl PR, Grutter MG, Robinson JA, Chembiochem. 2006 Mar;7(3):515-26. PMID:16511824
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