4OC7

Retinoic acid receptor alpha in complex with (E)-3-(3'-allyl-6-hydroxy-[1,1'-biphenyl]-3-yl)acrylic acid and a fragment of the coactivator TIF2

Summary for 4OC7

• Entry DOI: 10.2210/pdb4oc7/pdb
• Descriptor: Retinoic acid receptor RXR-alpha, Nuclear receptor coactivator 2, (2E)-3-[6-hydroxy-3'-(prop-2-en-1-yl)biphenyl-3-yl]prop-2-enoic acid, ... (4 entities in total)
• Functional Keywords: ligand binding domain, transcription
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus : P19793 Q15596
• Total number of polymer chains: 2
• Total formula weight: 30132.72

Authors

Leysen, S.,Scheepstra, M.,Brunsveld, L.,Milroy, L.G.,Ottmann, C. (deposition date: 2014-01-08, release date: 2014-10-08, Last modification date: 2024-02-28)

Primary citation

Scheepstra, M.,Nieto, L.,Hirsch, A.K.,Fuchs, S.,Leysen, S.,Lam, C.V.,in het Panhuis, L.,van Boeckel, C.A.,Wienk, H.,Boelens, R.,Ottmann, C.,Milroy, L.G.,Brunsveld, L.
A natural-product switch for a dynamic protein interface.
Angew.Chem.Int.Ed.Engl., 53:6443-6448, 2014

PubMed 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.

PubMed: 24821627
DOI: 10.1002/anie.201403773

Experimental method

X-RAY DIFFRACTION (2.5 Å)