Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/114984
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dc.contributor.authorFrkic, R.L.en
dc.contributor.authorMarshall, A.C.en
dc.contributor.authorBlayo, A.-.L.en
dc.contributor.authorPukala, T.L.en
dc.contributor.authorKamenecka, T.M.en
dc.contributor.authorGriffin, P.R.en
dc.contributor.authorBruning, J.B.en
dc.date.issued2018en
dc.identifier.citationiScience, 2018; 5:69-79en
dc.identifier.issn2589-0042en
dc.identifier.issn2589-0042en
dc.identifier.urihttp://hdl.handle.net/2440/114984-
dc.description.abstractPeroxisome 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.en
dc.description.statementofresponsibilityRebecca L. Frkic, Andrew C. Marshall, Anne-Laure Blayo, Tara L. Pukala, Theodore M. Kamenecka, Patrick R. Griffin, and John B. Bruningen
dc.language.isoenen
dc.publisherElsevieren
dc.rights© 2018 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).en
dc.titlePPARγ in complex with an antagonist and inverse agonist: a tumble and trap mechanism of the activation helixen
dc.title.alternativePPARgamma in complex with an antagonist and inverse agonist: a tumble and trap mechanism of the activation helixen
dc.typeJournal articleen
dc.identifier.rmid0030099421en
dc.identifier.doi10.1016/j.isci.2018.06.012en
dc.identifier.pubid441373-
pubs.library.collectionEarth and Environmental Sciences publicationsen
pubs.library.teamDS05en
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
dc.identifier.orcidMarshall, A.C. [0000-0002-9770-4594]en
dc.identifier.orcidPukala, T.L. [0000-0001-7391-1436]en
dc.identifier.orcidBruning, J.B. [0000-0002-6919-1824]en
Appears in Collections:IPAS publications
Earth and Environmental Sciences publications

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