Abstract
The crystal structure of a heterodimer between the ligand-binding domains (LBDs) of the human RARalpha bound to a selective antagonist and the constitutively active mouse RXRalphaF318A mutant shows that, pushed by a bulky extension of the ligand, RARalpha helix H12 adopts an antagonist position. The unexpected presence of a fatty acid in the ligand-binding pocket of RXRalpha(F318A is likely to account for its apparent "constitutivity." Specific conformational changes suggest the structural basis of pure and partial antagonism. The RAR-RXR heterodimer interface is similar to that observed in most nuclear receptor (NR) homodimers. A correlative analysis of 3D structures and sequences provides a novel view on dimerization among members of the nuclear receptor superfamily.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Benzoates / pharmacology
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Binding Sites
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Crystallography, X-Ray
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Dimerization
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Fatty Acids / isolation & purification
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Humans
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Ligands
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Mice
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Models, Molecular
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Molecular Sequence Data
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Receptors, Retinoic Acid / antagonists & inhibitors
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Receptors, Retinoic Acid / chemistry*
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Receptors, Retinoic Acid / genetics
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Recombinant Proteins / chemistry
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Retinoic Acid Receptor alpha
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Retinoid X Receptors
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Retinoids / pharmacology
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Signal Transduction
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Surface Properties
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Transcription Factors / chemistry*
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Transcription Factors / genetics
Substances
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Benzoates
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Fatty Acids
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Ligands
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RARA protein, human
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Rara protein, mouse
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Receptors, Retinoic Acid
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Recombinant Proteins
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Retinoic Acid Receptor alpha
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Retinoid X Receptors
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Retinoids
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Transcription Factors
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SR 11237