Dataset Information

PPAR? in Complex with an Antagonist and Inverse Agonist: a Tumble and Trap Mechanism of the Activation Helix.

ABSTRACT: Peroxisome proliferator activated receptor ? (PPAR?) is a nuclear receptor and target for antidiabetics that increase insulin sensitivity. Owing to the side effects of PPAR? full agonists, research has recently focused on non-activating ligands of PPAR?, 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 PPAR? 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 PPAR? alternatively trap H12 in an inactive configuration, which we have termed the tumble and trap mechanism.

SUBMITTER: Frkic RL

PROVIDER: S-EPMC6095676 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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PPARγ in Complex with an Antagonist and Inverse Agonist: a Tumble and Trap Mechanism of the Activation Helix.

Frkic Rebecca L RL Marshall Andrew C AC Blayo Anne-Laure AL Pukala Tara L TL Kamenecka Theodore M TM Griffin Patrick R PR Bruning John B JB

iScience 20180201

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 swit ...[more]

PMID: 30123887

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Project description:Background and purposeAdenosine may be generated by hydrolysis of extracellular nucleotides by ectonucleotidases, including ectonucleoside triphosphate diphosphohydrolase 1 (CD39), ecto-5'-nucleotidase (CD73), nucleotide pyrophosphatase phosphodiesterase 1 (NPP-1) and tissue non-specific alkaline phosphatase (TNAP). Previous work from our laboratory has uncovered a critical role for adenosine A1 receptors (A1 R) in osteoclastogenesis; blockade or deletion of these receptors diminishes osteoclast differentiation. Interestingly, selective A1 R agonists neither affect basal osteoclastogenesis nor do they reverse A1 R antagonist-mediated inhibition of osteoclastogenesis. In this study, we determined whether ectonucleotidase-mediated adenosine production was required for A1 R antagonist-mediated inhibition, and, when we saw no effect, determined whether A1 R was constitutively activated and the antagonist was acting as an inverse agonist to diminish osteoclast differentiation.Experimental approachOsteoclast formation derived from wild-type, CD39 knockout (KO), CD73 KO, NPP-1 KO and TNAP KO mice was examined by tartrate-resistant acid phosphatase staining of receptor activator of NF-κB ligand-macrophage colony-stimulating factor-stimulated osteoclasts and osteoclast gene expression (Ctsk, Acp5, MMP-9 and NFATc1). Intracellular cAMP concentration was determined by elisa.Key resultsRolofylline inhibited osteoclast formation in a dose-dependent manner (IC50 = 20-70 nM) in mice lacking all four of these phosphatases, although baseline osteoclast formation was significantly less in precursors from CD73 KO mice. Rolofylline (1 μM) stimulates cAMP production in bone marrow macrophages by 10.23 ± 0.89-fold.Conclusions and implicationsBased on these findings, we hypothesize that the A1 R is constitutively activated in osteoclast precursors, thereby diminishing basal AC activity, and that A1 R antagonists act as inverse agonists to release A1 R-mediated inhibition of basal AC activity and permit osteoclast differentiation. The constitutive activity of A1 R promotes osteoclast formation and down-regulation of this activity blocks osteoclast formation.

Dataset Information

PPAR? in Complex with an Antagonist and Inverse Agonist: a Tumble and Trap Mechanism of the Activation Helix.

Publications

PPARγ in Complex with an Antagonist and Inverse Agonist: a Tumble and Trap Mechanism of the Activation Helix.

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