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

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.
PDB ID: 4OC7Download
MMDB ID: 123613
PDB Deposition Date: 2014/1/8
Updated in MMDB: 2017/12
Experimental Method:
x-ray diffraction
Resolution: 2.5  Å
Source Organism:
Homo sapiens
Similar Structures:
Biological Unit for 4OC7: dimeric; determined by author and by software (PISA)
Molecular Components in 4OC7
Label Count Molecule
Proteins (2 molecules)
Retinoic Acid Receptor Rxr-alpha(Gene symbol: RXRA)
Molecule annotation
Nuclear Receptor Coactivator 2(Gene symbol: NCOA2)
Molecule annotation
Chemical (1 molecule)
* Click molecule labels to explore molecular sequence information.

Citing MMDB