1xap
Structure of the ligand binding domain of the Retinoic Acid Receptor beta
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OverviewOverview
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.
DiseaseDisease
Known disease associated with this structure: Camptodactyly-arthropathy-coxa vara-pericarditis syndrome OMIM:[604283]
About this StructureAbout this Structure
1XAP is a Single protein structure of sequence from Homo sapiens with TTB as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Rational design of RAR-selective ligands revealed by RARbeta crystal stucture., Germain P, Kammerer S, Perez E, Peluso-Iltis C, Tortolani D, Zusi FC, Starrett J, Lapointe P, Daris JP, Marinier A, de Lera AR, Rochel N, Gronemeyer H, EMBO Rep. 2004 Sep;5(9):877-82. PMID:15319780
Page seeded by OCA on Mon Nov 12 20:02:50 2007