2AXI

HDM2 in complex with a beta-hairpin

Summary for 2AXI

• Entry DOI: 10.2210/pdb2axi/pdb
• Related PRD ID: PRD_000326
• Descriptor: Ubiquitin-protein ligase E3 Mdm2, cyclic 8-mer peptide, SULFATE ION, ... (5 entities in total)
• Functional Keywords: p53, drug design, protein-protein interactions, ligase, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 15165.55

Authors

Mittl, P.R.E.,Fasan, R.,Robinson, J.,Gruetter, M.G. (deposition date: 2005-09-05, release date: 2006-03-21, Last modification date: 2023-08-23)

Primary citation

Fasan, R.,Dias, R.L.,Moehle, K.,Zerbe, O.,Obrecht, D.,Mittl, P.R.,Robinson, J.A.
Structure-Activity Studies in a Family of beta-Hairpin Protein Epitope Mimetic Inhibitors of the p53-HDM2 Protein-Protein Interaction.
Chembiochem, 7:515-526, 2006

PubMed Abstract: 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.

PubMed: 16511824
DOI: 10.1002/cbic.200500452

Experimental method

X-RAY DIFFRACTION (1.4 Å)