2axi

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[[Image:2axi.gif|left|200px]]
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{{Seed}}
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{{STRUCTURE_2axi| PDB=2axi | SCENE= }}
{{STRUCTURE_2axi| PDB=2axi | SCENE= }}
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'''HDM2 in complex with a beta-hairpin'''
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===HDM2 in complex with a beta-hairpin===
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==Overview==
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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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The line below this paragraph, {{ABSTRACT_PUBMED_16511824}}, adds the Publication Abstract to the page
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(as it appears on PubMed at http://www.pubmed.gov), where 16511824 is the PubMed ID number.
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{{ABSTRACT_PUBMED_16511824}}
==About this Structure==
==About this Structure==
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[[Category: P53]]
[[Category: P53]]
[[Category: Protein-protein interaction]]
[[Category: Protein-protein interaction]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 19:35:44 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 12:29:59 2008''

Revision as of 09:30, 29 July 2008

Image:2axi.png

Template:STRUCTURE 2axi

HDM2 in complex with a beta-hairpin

Template:ABSTRACT PUBMED 16511824

About this Structure

2AXI is a Single protein structure of sequence from Homo sapiens. 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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