1MZN

CRYSTAL STRUCTURE at 1.9 ANGSTROEMS RESOLUTION OF THE HOMODIMER OF HUMAN RXR ALPHA LIGAND BINDING DOMAIN BOUND TO THE SYNTHETIC AGONIST COMPOUND BMS 649 AND A COACTIVATOR PEPTIDE

Summary for 1MZN

• Entry DOI: 10.2210/pdb1mzn/pdb
• Related: 1FBY 1MV9 1MVC
• Descriptor: RXR retinoid X receptor, Nuclear receptor coactivator 2, 4-[2-(5,5,8,8-TETRAMETHYL-5,6,7,8-TETRAHYDRO-NAPHTHALEN-2-YL)-[1,3]DIOXOLAN-2-YL]-BENZOIC ACID, ... (4 entities in total)
• Functional Keywords: transcription, nuclear receptor, retinoic acid receptors, agonist
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P19793 Q15596
• Total number of polymer chains: 8
• Total formula weight: 115261.50

Authors

Egea, P.F.,Mitschler, A.,Moras, D. (deposition date: 2002-10-09, release date: 2002-10-23, Last modification date: 2023-10-25)

Primary citation

Egea, P.F.,Mitschler, A.,Moras, D.
Molecular Recognition of Agonist Ligands by RXRs
MOL.ENDOCRINOL., 16:987-997, 2002

PubMed Abstract: 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.

PubMed: 11981034
DOI: 10.1210/me.16.5.987

Experimental method

X-RAY DIFFRACTION (1.9 Å)