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Type: Journal article
Title: PPARγ in complex with an antagonist and inverse agonist: a tumble and trap mechanism of the activation helix
Other Titles: PPARgamma in complex with an antagonist and inverse agonist: a tumble and trap mechanism of the activation helix
Author: Frkic, R.L.
Marshall, A.C.
Blayo, A.-.L.
Pukala, T.L.
Kamenecka, T.M.
Griffin, P.R.
Bruning, J.B.
Citation: iScience, 2018; 5:69-79
Publisher: Elsevier
Issue Date: 2018
ISSN: 2589-0042
Statement of
Rebecca L. Frkic, Andrew C. Marshall, Anne-Laure Blayo, Tara L. Pukala, Theodore M. Kamenecka, Patrick R. Griffin, and John B. Bruning
Abstract: Peroxisome proliferator activated receptor γ (PPARγ) is a nuclear receptor and target for antidiabetics that increase insulin sensitivity. Owing to the side effects of PPARγ full agonists, research has recently focused on non-activating ligands of PPARγ, which increase insulin sensitivity with decreased side effects. Here, we present the crystal structures of inverse agonist SR10171 and a chemically related antagonist SR11023 bound to the PPARγ ligand-binding domain, revealing an allosteric switch in the activation helix, helix 12 (H12), forming an antagonist conformation in the receptor. H12 interacts with the antagonists to become fixed in an alternative location. Native mass spectrometry indicates that this prevents contacts with coactivator peptides and allows binding of corepressor peptides. Antagonists of related nuclear receptors act to sterically prevent the active configuration of H12, whereas these antagonists of PPARγ alternatively trap H12 in an inactive configuration, which we have termed the tumble and trap mechanism.
Rights: © 2018 The Author(s). This is an open access article under the CC BY-NC-ND license (
RMID: 0030099421
DOI: 10.1016/j.isci.2018.06.012
Appears in Collections:IPAS publications
Earth and Environmental Sciences publications

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