Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors.
Mol Cell
; 5(3): 545-55, 2000 Mar.
Article
de En
| MEDLINE
| ID: mdl-10882139
ABSTRACT
The nuclear receptor PPARgamma/RXRalpha heterodimer regulates glucose and lipid homeostasis and is the target for the antidiabetic drugs GI262570 and the thiazolidinediones (TZDs). We report the crystal structures of the PPARgamma and RXRalpha LBDs complexed to the RXR ligand 9-cis-retinoic acid (9cRA), the PPARgamma agonist rosiglitazone or GI262570, and coactivator peptides. The PPARgamma/RXRalpha heterodimer is asymmetric, with each LBD deviated approximately 10 degrees from the C2 symmetry, allowing the PPARgamma AF-2 helix to interact with helices 7 and 10 of RXRalpha. The heterodimer interface is composed of conserved motifs in PPARgamma and RXRalpha that form a coiled coil along helix 10 with additional charge interactions from helices 7 and 9. The structures provide a molecular understanding of the ability of RXR to heterodimerize with many nuclear receptors and of the permissive activation of the PPARgamma/RXRbeta heterodimer by 9cRA.
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Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Facteurs de transcription
/
Protéines nucléaires
/
Récepteurs à l'acide rétinoïque
/
Récepteurs cytoplasmiques et nucléaires
/
Thiazolidinediones
Type d'étude:
Prognostic_studies
Limites:
Humans
Langue:
En
Journal:
Mol Cell
Sujet du journal:
BIOLOGIA MOLECULAR
Année:
2000
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique