Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors.
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.
Gampe
R T
RT
Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA.
Montana
V G
VG
Lambert
M H
MH
Miller
A B
AB
Bledsoe
R K
RK
Milburn
M V
MV
Kliewer
S A
SA
Willson
T M
TM
Xu
H E
HE
D000077556:Alitretinoin; D000595:Amino Acid Sequence; D001665:Binding Sites; D003461:Crystallography; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D019281:Dimerization; D015195:Drug Design; D051548:Histone Acetyltransferases; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry*; D056920:Nuclear Receptor Coactivator 1; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000737:chemistry*; D018168:Receptors, Retinoic Acid / Q000737:chemistry*; D047488:Retinoid X Receptors; D000077154:Rosiglitazone; D017386:Sequence Homology, Amino Acid; D013499:Surface Properties; D013844:Thiazoles / Q000737:chemistry; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000737:chemistry*; D014212:Tretinoin / Q000737:chemistry
D008024:Ligands; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D000077556:Alitretinoin; D014212:Tretinoin; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1