1pcg

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spinqualitylabelsall models 1pcg, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The interaction between nuclear receptors and coactivators provides an, arena for testing whether protein-protein interactions may be inhibited by, small molecule drug candidates. We provide evidence that a short cyclic, peptide, containing a copy of the LXXLL nuclear receptor box pentapeptide, binds tightly and selectively to estrogen receptor alpha. Furthermore, as, shown by x-ray analysis, the disulfide-bridged nonapeptide, nonhelical in, aqueous solutions, is able to adopt a quasihelical conformer while binding, to the groove created by ligand attachment to estrogen receptor alpha. An, i, i+3 linked analog, H-Lys-cyclo(d-Cys-Ile-Leu-Cys)-Arg-Leu-Leu-Gln-NH2, (peptidomimetic estrogen receptor modulator 1), binds with a Ki of 25 nM, significantly better than an i, i+4 bridged cyclic amide, as predicted by, molecular modeling design criteria. The induction of helical character, effective binding, and receptor selectivity exhibited by this peptide, analog provide strong support for this strategy. The stabilization of, minimalist surface motifs may prove useful for the control of other, macromolecular assemblies, especially when an amphiphilic helix is crucial, for the strong binding interaction between two proteins.

Disease

Known diseases associated with this structure: Atherosclerosis, susceptibility to OMIM:[133430], Breast cancer OMIM:[133430], Estrogen resistance OMIM:[133430], HDL response to hormone replacement, augmented OMIM:[133430], Migraine, susceptibility to OMIM:[133430], Myocardial infarction, susceptibility to OMIM:[133430]

About this Structure

1PCG is a Single protein structure of sequence from Homo sapiens with EST as ligand. Full crystallographic information is available from OCA.

Reference

Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions., Leduc AM, Trent JO, Wittliff JL, Bramlett KS, Briggs SL, Chirgadze NY, Wang Y, Burris TP, Spatola AF, Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11273-8. Epub 2003 Sep 17. PMID:13679575

Page seeded by OCA on Mon Nov 12 18:42:08 2007