- Thrombin receptor-activating peptides (TRAPs): Investigation of bioactive conformations via structure-activity, spectroscopic, and computational studies
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The thrombin receptor (PAR-1) is an unusual transmembrane G-protein coupled receptor in that it is activated by serine protease cleavage of its extracellular N-terminus to expose an agonist peptide ligand, which is tethered to the receptor itself. Synthet
- Ceruso, Marco A.,McComsey, David F.,Leo, Gregory C.,Andrade-Gordon, Patricia,Addo, Michael F.,Scarborough, Robert M.,Oksenberg, Donna,Maryanoff, Bruce E.
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- Novel selective inhibitors of the interaction of individual nuclear hormone receptors with a mutually shared steroid receptor coactivator 2
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Nuclear hormone receptor (NR) signaling, currently a therapeutic target in multiple diseases, involves an ordered series of protein interactions to regulate transcription in response to changing hormone levels. Later steps in the process of ligand-dependent signaling are driven by a highly conserved interaction between the NRs and the steroid receptor coactivators (SRCs) that is effected by a conserved interaction motif (L1XXL2L3), known as an NR box. Using computational design and combinatorial chemistry, we have produced novel ∞-helical proteomimetics of the second NR box of SRC2 that exploit structural differences between human estrogen receptor ∞ (hER∞), human estrogen receptor β (hERβ), and human thyroid hormone receptor β (hTRβ). The resulting library sequentially replaced each leucine with non-natural side chains. Screening this library using a quantitative competition assay revealed compounds that selectively inhibit the interaction of SRC2-2 with each individual NR in preference to its interaction with the other NR. This approach generated highly selective compounds from one that had no specificity for a particular family member. These compounds represent the first family-member-selective competitive inhibitors of the protein interactions of transcription factors. Copyright
- Geistlinger, Timothy R.,Guy, R. Kiplin
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p. 6852 - 6853
(2007/10/03)
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