Structure-activity studies in a family of beta-hairpin protein epitope mimetic inhibitors of the p53-HDM2 protein-protein interaction.
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.
Fasan
Rudi
R
Institute of Organic Chemistry, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
Dias
Ricardo L A
RL
Moehle
Kerstin
K
Zerbe
Oliver
O
Obrecht
Daniel
D
Mittl
Peer R E
PR
Grütter
Markus G
MG
Robinson
John A
JA
D000595:Amino Acid Sequence; D003460:Crystallization; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology*; D008958:Models, Molecular; D018716:Molecular Mimicry; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011487:Protein Conformation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*
D000939:Epitopes; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2