2axi

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[[Image:2axi.gif|left|200px]]
[[Image:2axi.gif|left|200px]]
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{{Structure
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|PDB= 2axi |SIZE=350|CAPTION= <scene name='initialview01'>2axi</scene>, resolution 1.40&Aring;
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The line below this paragraph, containing "STRUCTURE_2axi", creates the "Structure Box" on the page.
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|SITE=
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <scene name='pdbligand=6CW:6-CHLORO-L-TRYPTOPHAN'>6CW</scene>, <scene name='pdbligand=DPR:D-PROLINE'>DPR</scene>, <scene name='pdbligand=MPO:3[N-MORPHOLINO]PROPANE+SULFONIC+ACID'>MPO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>
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or leave the SCENE parameter empty for the default display.
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|GENE= MDM2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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|DOMAIN=
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{{STRUCTURE_2axi| PDB=2axi | SCENE= }}
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|RELATEDENTRY=
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2axi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2axi OCA], [http://www.ebi.ac.uk/pdbsum/2axi PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2axi RCSB]</span>
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'''HDM2 in complex with a beta-hairpin'''
'''HDM2 in complex with a beta-hairpin'''
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[[Category: Mittl, P R.E.]]
[[Category: Mittl, P R.E.]]
[[Category: Robinson, J.]]
[[Category: Robinson, J.]]
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[[Category: drug design]]
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[[Category: Drug design]]
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[[Category: p53]]
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[[Category: P53]]
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[[Category: protein-protein interaction]]
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[[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 Mon Mar 31 01:58:37 2008''
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Revision as of 16:35, 3 May 2008

Image:2axi.gif

Template:STRUCTURE 2axi

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. 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 Page seeded by OCA on Sat May 3 19:35:44 2008

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