Asymmetry in the PPARγ/RXRα crystal structure reveals the molecular basis of heterodimerization among nuclear receptors

Robert T. Gampe, Valerie G. Montana, Millard H. Lambert, Aaron B. Miller, Randy K. Bledsoe, Michael V. Milburn, Steven A. Kliewer, Timothy M. Willson, H. Eric Xu

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Abstract

The nuclear receptor PPARγ/RXRα heterodimer regulates glucose and lipid homeostasis and is the target for the antidiabetic drugs GI262570 and the thiazoli-dinediones (TZDs). We report the crystal structures of the PPARγ and RXRα LBDs complexed to the RXR ligand 9-cis-retinoic acid (9cRA), the PP ARγ agonist rosiglitazone or GI262570, and coactivator peptides. The PPARγ/RXRα heterodimer is asymmetric, with each LBD deviated ~10°from the C2 symmetry, allowing the PPARγ AF-2 helix to interact with helices 7 and 10 of RXRα. The heterodimer interface is composed of conserved motifs in PPARγ and RXRα 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 PPARγ/RXRα heterodimer by 9cRA.

Original languageEnglish (US)
Pages (from-to)545-555
Number of pages11
JournalMolecular Cell
Volume5
Issue number3
StatePublished - 2000

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Peroxisome Proliferator-Activated Receptors
Cytoplasmic and Nuclear Receptors
Molecular Structure
rosiglitazone
Furylfuramide
Hypoglycemic Agents
Homeostasis
Ligands
Lipids
Glucose
Peptides

ASJC Scopus subject areas

  • Molecular Biology

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Gampe, R. T., Montana, V. G., Lambert, M. H., Miller, A. B., Bledsoe, R. K., Milburn, M. V., ... Xu, H. E. (2000). Asymmetry in the PPARγ/RXRα crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Molecular Cell, 5(3), 545-555.

Asymmetry in the PPARγ/RXRα crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. / Gampe, Robert T.; Montana, Valerie G.; Lambert, Millard H.; Miller, Aaron B.; Bledsoe, Randy K.; Milburn, Michael V.; Kliewer, Steven A.; Willson, Timothy M.; Xu, H. Eric.

In: Molecular Cell, Vol. 5, No. 3, 2000, p. 545-555.

Research output: Contribution to journalArticle

Gampe, RT, Montana, VG, Lambert, MH, Miller, AB, Bledsoe, RK, Milburn, MV, Kliewer, SA, Willson, TM & Xu, HE 2000, 'Asymmetry in the PPARγ/RXRα crystal structure reveals the molecular basis of heterodimerization among nuclear receptors', Molecular Cell, vol. 5, no. 3, pp. 545-555.
Gampe RT, Montana VG, Lambert MH, Miller AB, Bledsoe RK, Milburn MV et al. Asymmetry in the PPARγ/RXRα crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Molecular Cell. 2000;5(3):545-555.
Gampe, Robert T. ; Montana, Valerie G. ; Lambert, Millard H. ; Miller, Aaron B. ; Bledsoe, Randy K. ; Milburn, Michael V. ; Kliewer, Steven A. ; Willson, Timothy M. ; Xu, H. Eric. / Asymmetry in the PPARγ/RXRα crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. In: Molecular Cell. 2000 ; Vol. 5, No. 3. pp. 545-555.
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AU - Bledsoe, Randy K.

AU - Milburn, Michael V.

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AB - The nuclear receptor PPARγ/RXRα heterodimer regulates glucose and lipid homeostasis and is the target for the antidiabetic drugs GI262570 and the thiazoli-dinediones (TZDs). We report the crystal structures of the PPARγ and RXRα LBDs complexed to the RXR ligand 9-cis-retinoic acid (9cRA), the PP ARγ agonist rosiglitazone or GI262570, and coactivator peptides. The PPARγ/RXRα heterodimer is asymmetric, with each LBD deviated ~10°from the C2 symmetry, allowing the PPARγ AF-2 helix to interact with helices 7 and 10 of RXRα. The heterodimer interface is composed of conserved motifs in PPARγ and RXRα 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 PPARγ/RXRα heterodimer by 9cRA.

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