Crystal structure of a heterodimeric complex of RAR and RXR ligand-binding domains.
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.
Bourguet
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W
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CRNS/INSERM/Université Louis Pasteur/Collège de France, Illkirch, Strasbourg.
Vivat
V
V
Wurtz
J M
JM
Chambon
P
P
Gronemeyer
H
H
Moras
D
D
D000595:Amino Acid Sequence; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D005227:Fatty Acids / Q000302:isolation & purification; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology; D015398:Signal Transduction; D013499:Surface Properties; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics
D001565:Benzoates; D005227:Fatty Acids; D008024:Ligands; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors; C087130:SR 11237