title: A natural-product switch for a dynamic protein interface.
abstract: 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.
authors.affiliation: Laboratory of Chemical Biology and Institute of Complex Molecular Systems (ICMS), Department of Biomedical Engineering, Technische Universiteit Eindhoven, Den Dolech 2, 5612 AZ Eindhoven (The Netherlands) http://www.tue.nl/cb.
authors.forename: Marcel
authors.initials: M
authors.lastname: Scheepstra
authors.forename: Lidia
authors.initials: L
authors.lastname: Nieto
authors.forename: Anna K H
authors.initials: AK
authors.lastname: Hirsch
authors.forename: Sascha
authors.initials: S
authors.lastname: Fuchs
authors.forename: Seppe
authors.initials: S
authors.lastname: Leysen
authors.forename: Chan Vinh
authors.initials: CV
authors.lastname: Lam
authors.forename: Leslie
authors.initials: L
authors.lastname: in het Panhuis
authors.forename: Constant A A
authors.initials: CA
authors.lastname: van Boeckel
authors.forename: Hans
authors.initials: H
authors.lastname: Wienk
authors.forename: Rolf
authors.initials: R
authors.lastname: Boelens
authors.forename: Christian
authors.initials: C
authors.lastname: Ottmann
authors.forename: Lech-Gustav
authors.initials: LG
authors.lastname: Milroy
authors.forename: Luc
authors.initials: L
authors.lastname: Brunsveld
mesh_terms: D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry*; D001713:Biphenyl Compounds / Q000737:chemistry; D018360:Crystallography, X-Ray; D008024:Ligands; D017705:Lignans / Q000737:chemistry; D008954:Models, Biological; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry*; D047488:Retinoid X Receptors / Q000737:chemistry; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D001688:Biological Products; D001713:Biphenyl Compounds; D008024:Ligands; D017705:Lignans; D018160:Receptors, Cytoplasmic and Nuclear; D047488:Retinoid X Receptors; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols
keywords: drug discovery; natural products; nuclear receptors; protein-protein interactions; retinoid X receptor