A Natural-Product Switch for a Dynamic Protein Interface

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. Curren...

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Vydané v:	Angewandte Chemie International Edition Ročník 53; číslo 25; s. 6443 - 6448
Hlavní autori:	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, Lech-Gustav, Brunsveld, Luc
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Weinheim WILEY-VCH Verlag 16.06.2014 WILEY‐VCH Verlag Wiley Wiley Subscription Services, Inc
Vydanie:	International ed. in English
Predmet:	Binding Binding Sites Biological Products - chemistry Biphenyl Compounds - chemistry Chemical synthesis Chemistry Chemistry, Multidisciplinary Crystallography Crystallography, X-Ray drug discovery Dynamics Inhibitors Interfaces Ligands Lignans - chemistry Magnetic resonance spectroscopy Mathematical models Models, Biological Natural products NMR NMR spectroscopy Nuclear magnetic resonance nuclear receptors Physical Sciences protein-protein interactions Proteins Receptors Receptors, Cytoplasmic and Nuclear - chemistry retinoid X receptor Retinoid X receptors Retinoid X Receptors - chemistry Science & Technology Screening Transcription retinoid X receptor ANDROGEN RECEPTOR NUCLEAR MODULATORS COACTIVATOR BINDING ESTROGEN-RECEPTOR protein-protein interactions nuclear receptors natural products drug discovery SMALL-MOLECULE INHIBITORS BIOLOGICAL EVALUATION RETINOID-X-RECEPTOR THYROID-HORMONE RECEPTOR
ISSN:	1433-7851, 1521-3773, 1521-3773
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Popis
Shrnutí:	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. Rational splitting of the dual‐binding properties of a natural product delivers two mechanistically different ligands, which selectively target opposite sides of a dynamic protein interface (see picture; AF2=activation function 2). This work highlights the value of screening natural products against transient protein complexes.
Bibliografia:	Netherlands Organisation for Scientific Research - No. 711011017 ark:/67375/WNG-Z2PVJGPC-T istex:C97E9F088D7364EE6230568452C7C9CAD141DF72 ArticleID:ANIE201403773 We thank Nicky Hoek, Dr. Eric Kalkhoven and Dr. Arjen Koppen (UMC, Utrecht, The Netherlands) for their scientific support. Funding was granted by the Netherlands Organisation for Scientific Research via Gravity program 024.001.035, ECHO grant 711011017, VENI grant to A.K.H.H., and a Marie Curie Action (PIEF-GA-2011-298489 to LN). We thank Nicky Hoek, Dr. Eric Kalkhoven and Dr. Arjen Koppen (UMC, Utrecht, The Netherlands) for their scientific support. Funding was granted by the Netherlands Organisation for Scientific Research via Gravity program 024.001.035, ECHO grant 711011017, VENI grant to A.K.H.H., and a Marie Curie Action (PIEF‐GA‐2011‐298489 to LN). ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1433-7851 1521-3773 1521-3773
DOI:	10.1002/anie.201403773