Source:http://linkedlifedata.com/resource/pubmed/id/16511824
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
3
|
| pubmed:dateCreated |
2006-3-8
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| pubmed:abstractText |
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.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical | |
| pubmed:status |
MEDLINE
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| pubmed:month |
Mar
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| pubmed:issn |
1439-4227
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:volume |
7
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
515-26
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| pubmed:meshHeading |
pubmed-meshheading:16511824-Amino Acid Sequence,
pubmed-meshheading:16511824-Crystallization,
pubmed-meshheading:16511824-Epitopes,
pubmed-meshheading:16511824-Models, Molecular,
pubmed-meshheading:16511824-Molecular Mimicry,
pubmed-meshheading:16511824-Nuclear Magnetic Resonance, Biomolecular,
pubmed-meshheading:16511824-Protein Binding,
pubmed-meshheading:16511824-Protein Conformation,
pubmed-meshheading:16511824-Proto-Oncogene Proteins c-mdm2,
pubmed-meshheading:16511824-Structure-Activity Relationship,
pubmed-meshheading:16511824-Tumor Suppressor Protein p53
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| pubmed:year |
2006
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| pubmed:articleTitle |
Structure-activity studies in a family of beta-hairpin protein epitope mimetic inhibitors of the p53-HDM2 protein-protein interaction.
|
| pubmed:affiliation |
Institute of Organic Chemistry, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
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| pubmed:publicationType |
Journal Article
|