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A Natural‐Product Switch for a Dynamic Protein Interface
Author(s) -
Scheepstra Marcel,
Nieto Lidia,
Hirsch Anna K. H.,
Fuchs Sascha,
Leysen Seppe,
Lam Chan Vinh,
in het Panhuis Leslie,
van Boeckel Constant A. A.,
Wienk Hans,
Boelens Rolf,
Ottmann Christian,
Milroy LechGustav,
Brunsveld Luc
Publication year - 2014
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201403773
Subject(s) - coactivator , retinoid x receptor , natural product , chemistry , nuclear receptor coactivator 2 , ligand (biochemistry) , biophysics , nuclear receptor , transcription factor , stereochemistry , biochemistry , receptor , biology , gene
Small ligands are a powerful way to control the function of protein complexes via dynamic binding interfaces. The classic example is found in gene transcription where small ligands regulate nuclear receptor binding to coactivator proteins via the dynamic activation function 2 (AF2) interface. Current ligands target the ligand‐binding pocket side of the AF2. Few ligands are known, which selectively target the coactivator side of the AF2, or which can be selectively switched from one side of the interface to the other. We use NMR spectroscopy and modeling to identify a natural product, which targets the retinoid X receptor (RXR) at both sides of the AF2. We then use chemical synthesis, cellular screening and X‐ray co‐crystallography to split this dual activity, leading to a potent and molecularly efficient RXR agonist, and a first‐of‐kind inhibitor selective for the RXR/coactivator interaction. Our findings justify future exploration of natural products at dynamic protein interfaces.