4DM8

Crystal structure of RARb LBD in complex with 9cis retinoic acid

Summary for 4DM8

• Entry DOI: 10.2210/pdb4dm8/pdb
• Related: 1XAP 4DM6 4DMA
• Descriptor: Retinoic acid receptor beta, Nuclear receptor coactivator 1, RETINOIC ACID, ... (4 entities in total)
• Functional Keywords: nuclear receptor, rarb, 9cis retinoic acid, alpha helical sandwich, transcription factor, retinoic acid, transcription-protein binding complex, transcription/protein binding
• Biological source: Homo sapiens (human); More
• Cellular location: Isoform Beta-1: Nucleus. Isoform Beta-2: Nucleus. Isoform Beta-4: Cytoplasm: P10826; Nucleus : Q15788
• Total number of polymer chains: 4
• Total formula weight: 66571.12

Authors

Osz, J.,Br livet, Y.,Peluso-Iltis, C.,Cura, V.,Eiler, S.,Ruff, M.,Bourguet, W.,Rochel, N.,Moras, D. (deposition date: 2012-02-07, release date: 2012-03-07, Last modification date: 2024-02-28)

Primary citation

Osz, J.,Brelivet, Y.,Peluso-Iltis, C.,Cura, V.,Eiler, S.,Ruff, M.,Bourguet, W.,Rochel, N.,Moras, D.
Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors.
Proc.Natl.Acad.Sci.USA, 109:E588-E594, 2012

PubMed Abstract: Transcription regulation by steroid hormones, vitamin derivatives, and metabolites is mediated by nuclear receptors (NRs), which play an important role in ligand-dependent gene expression and human health. NRs function as homodimers or heterodimers and are involved in a combinatorial, coordinated and sequentially orchestrated exchange between coregulators (corepressors, coactivators). The architecture of DNA-bound functional dimers positions the coregulators proteins. We previously demonstrated that retinoic acid (RAR-RXR) and vitamin D3 receptors (VDR-RXR) heterodimers recruit only one coactivator molecule asymmetrically without steric hindrance for the binding of a second cofactor. We now address the problem of homodimers for which the presence of two identical targets enhances the functional importance of the mode of binding. Using structural and biophysical methods and RAR as a model, we could dissect the molecular mechanism of coactivator recruitment to homodimers. Our study reveals an allosteric mechanism whereby binding of a coactivator promotes formation of nonsymmetrical RAR homodimers with a 21 stoichiometry. Ligand conformation and the cofactor binding site of the unbound receptor are affected through the dimer interface. A similar control mechanism is observed with estrogen receptor (ER) thus validating the negative cooperativity model for an established functional homodimer. Correlation with published data on other NRs confirms the general character of this regulatory pathway.

PubMed: 22355136
DOI: 10.1073/pnas.1118192109

Experimental method

X-RAY DIFFRACTION (2.3 Å)