Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 100, Issue 20, Pages 11273-11278Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1934759100
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The interaction between nuclear receptors and coactivators provide; 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 a. 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-Gin-NH2 (pepcidomimetic estrogen receptor modulator 1), binds with a K-i 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.
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