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 ␣. 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 ␣. An i, i؉3 linked analog, H-Lys-cyclo(D-Cys-Ile-Leu-Cys)-Arg-Leu-Leu-Gln-NH 2 (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. M embers of the nuclear receptor (NR) superfamily, which include the steroid receptors, are ligand-activated transcription factors that regulate a wide variety of physiological and developmental processes (1-3). Upon ligand binding, steroid receptors shed their accompanying heat shock proteins to form homodimers, and bind to their cognate DNA elements within the regulatory regions of steroid responsive genes. Steroid receptor agonists are typically hydrophobic molecules and have been demonstrated to bind to a buried hydrophobic pocket within the carboxyterminal ligand-binding domain (LBD) of the receptor. This results in a conformational shift causing repositioning of helix 12, which allows for recognition of coactivator proteins. Many coactivators contain a short pentapeptide motif, known as a NR box (4), that is responsible for recognition of a hydrophobic groove created on the surface of the LBD in response to repositioning of helix 12 upon agonist binding (5). Steroid receptor antagonists, like agonists, are also hydrophobic molecules and bind within the core of the LBD; however, these ligands do not position helix 12 in the correct conformation that would allow the coactivators to recognize the receptor. A large number of proteins characterized as NR coactivators have been identified, and many appear to contain one or, in some cases, multiple copies of the NR box with the consensus sequence LXXLL. McDonnell and coworkers (6, 7) have noted that peptide sequences that mimic this NR interaction motif could function as ER antagonists in cell based models when overexpressed as a component of a fusion protein. Detailed analysis of the interactions between the receptor and coactivators has revealed new possible points of intervention (8). Such targets have recently been proposed as attractive options for new anticancer dr...

The surface complex [([triple bond]SiO)Re([triple bond]CtBu)(=CHtBu)(CH2tBu)] (1) is a highly efficient propene metathesis catalyst with high initial activities and a good productivity. However, it undergoes a fast deactivation process with time on stream, which is first order in active sites and ethene. Noteworthy, 1-butene and pentenes, unexpected products in the metathesis of propene, are formed as primary products, in large amount relative to Re (>>1 equiv/Re), showing that their formation is not associated with the formation of inactive species. DFT calculations on molecular model systems show that byproduct formation and deactivation start by a beta-H transfer trans to the weak sigma-donor ligand (siloxy) at the metallacyclobutane intermediate having a square-based pyramid geometry. This key step has an energy barrier slightly higher than that calculated for olefin metathesis. After beta-H transfer, the most accessible pathway is the insertion of ethene in the Re-H bond. The resulting pentacoordinated trisperhydrocarbyl complex rearranges via either (1) alpha-H abstraction yielding the unexpected 1-butene byproduct and the regeneration of the catalyst or (2) beta-H abstraction leading to degrafting. These deactivation and byproduct formation pathways are in full agreement with the experimental data.