1XAP

Structure of the ligand binding domain of the Retinoic Acid Receptor beta

Summary for 1XAP

• Entry DOI: 10.2210/pdb1xap/pdb
• Descriptor: Retinoic acid receptor beta, 4-[(1E)-2-(5,5,8,8-TETRAMETHYL-5,6,7,8-TETRAHYDRONAPHTHALEN-2-YL)PROP-1-ENYL]BENZOIC ACID (3 entities in total)
• Functional Keywords: nuclear receptor, ligand binding domain, retinoic acid receptor beta, ttnpb, transcription
• Biological source: Homo sapiens (human)
• Cellular location: Isoform Beta-1: Nucleus. Isoform Beta-2: Nucleus. Isoform Beta-4: Cytoplasm: P10826
• Total number of polymer chains: 1
• Total formula weight: 30527.44

Authors

Germain, P.,Kammerer, S.,Peluso-Iltis, C.,Tortolani, D.,Zusi, F.C.,Starrett, J.,Lapointe, P.,Daris, J.P.,Marinier, A.,De Lera, A.R.,Rochel, N.,Gronemeyer, H. (deposition date: 2004-08-26, release date: 2004-11-16, Last modification date: 2023-10-25)

Primary citation

Germain, P.,Kammerer, S.,Perez, E.,Peluso-Iltis, C.,Tortolani, D.,Zusi, F.C.,Starrett, J.,Lapointe, P.,Daris, J.P.,Marinier, A.,De Lera, A.R.,Rochel, N.,Gronemeyer, H.
Rational design of RAR-selective ligands revealed by RARbeta crystal structure
Embo Rep., 5:877-882, 2004

PubMed Abstract: The crystal structure of the ligand-binding domain of RARbeta, a suspect tumour suppressor, reveals important features that distinguish it from the two other RAR isotypes. The most striking difference is an extra cavity allowing RARbeta to bind more bulky agonists. Accordingly, we identified a ligand that shows RARbeta selectivity with a 100-fold higher affinity to RARbeta than to alpha or gamma isotypes. The structural differences between the three RAR ligand-binding pockets revealed a rationale explaining how a single retinoid can be at the same time an RARalpha, gamma antagonist and an RARbeta agonist. In addition, we demonstrate how to generate an RARbeta antagonist by gradually modifying the bulkiness of a single substitution. Together, our results provide structural guidelines for the synthesis of RARbeta-selective agonists and antagonists, allowing for the first time to address pharmacologically the tumour suppressor role of RARbeta in vitro and in animal models.

PubMed: 15319780
DOI: 10.1038/sj.embor.7400235

Experimental method

X-RAY DIFFRACTION (2.1 Å)