6C5T

PPARg LBD bound to SR11023

Summary for 6C5T

• Entry DOI: 10.2210/pdb6c5t/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, 2-{4-[(5-{[(1R)-1-(3-cyclopropylphenyl)ethyl]carbamoyl}-2,3-dimethyl-1H-indol-1-yl)methyl]phenyl}-2-methylpropanoic acid (3 entities in total)
• Functional Keywords: peroxisome proliferator activated receptor gamma; pparg, nuclear receptor, inverse agonist, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 32073.29

Authors

Bruning, J.B.,Frkic, R.L.,Griffin, P.R. (deposition date: 2018-01-16, release date: 2018-08-01, Last modification date: 2024-10-16)

Primary citation

Frkic, R.L.,Marshall, A.C.,Blayo, A.L.,Pukala, T.L.,Kamenecka, T.M.,Griffin, P.R.,Bruning, J.B.
PPAR gamma in Complex with an Antagonist and Inverse Agonist: a Tumble and Trap Mechanism of the Activation Helix.
iScience, 5:69-79, 2018

PubMed 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.

PubMed: 30123887
DOI: 10.1016/j.isci.2018.06.012

Experimental method

X-RAY DIFFRACTION (2.75 Å)