1mvc
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Crystal structure of the human RXR alpha ligand binding domain bound to the synthetic agonist compound BMS 649 and a coactivator peptide
OverviewOverview
The nuclear receptor RXR is an obligate partner in many signal, transduction pathways. We report the high-resolution structures of two, complexes of the human RXRalpha ligand-binding domain specifically bound, to two different and chemically unrelated agonist compounds: docosa, hexaenoic acid, a natural derivative of eicosanoic acid, present in, mammalian cells and recently identified as a potential endogenous RXR, ligand in the mouse brain, and the synthetic ligand BMS 649. In both, structures the RXR-ligand-binding domain forms homodimers and exhibits the, active conformation previously observed with 9-cis-RA. Analysis of the, differences in ligand-protein contacts (predominantly van der Waals, forces) and binding cavity geometries and volumes for the several, agonist-bound RXR structures clarifies the structural features important, for ligand recognition. The L-shaped ligand-binding pocket adapts to the, diverse ligands, especially at the level of residue N306, which might thus, constitute a new target for drug-design. Despite its highest affinity, 9-cis-RA displays the lowest number of ligand-protein contacts. These, structural results support the idea that docosa hexaenoic acid and related, fatty acids could be natural agonists of RXRs and question the real nature, of the endogenous ligand(s) in mammalian cells.
About this StructureAbout this Structure
1MVC is a Protein complex structure of sequences from Homo sapiens with BM6 as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Molecular recognition of agonist ligands by RXRs., Egea PF, Mitschler A, Moras D, Mol Endocrinol. 2002 May;16(5):987-97. PMID:11981034
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