3T03

Crystal structure of PPAR gamma ligand binding domain in complex with a novel partial agonist GQ-16

Summary for 3T03

• Entry DOI: 10.2210/pdb3t03/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, Nuclear receptor coactivator 1, (5Z)-5-(5-bromo-2-methoxybenzylidene)-3-(4-methylbenzyl)-1,3-thiazolidine-2,4-dione, ... (4 entities in total)
• Functional Keywords: protein-drug complex, thiazolidinediones, ligand binding protein, transcription factor, nucleus receptor, transcription-transcription regulator complex, transcription/transcription regulator
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P37231; Nucleus (By similarity): Q15788
• Total number of polymer chains: 4
• Total formula weight: 69874.53

Authors

Rajagopalan, S.,Webb, P.,Baxter, J.D.,Brennan, R.G.,Phillips, K.J. (deposition date: 2011-07-19, release date: 2012-05-23, Last modification date: 2023-09-13)

Primary citation

Amato, A.A.,Rajagopalan, S.,Lin, J.Z.,Carvalho, B.M.,Figueira, A.C.,Lu, J.,Ayers, S.D.,Mottin, M.,Silveira, R.L.,Souza, P.C.,Mourao, R.H.,Saad, M.J.,Togashi, M.,Simeoni, L.A.,Abdalla, D.S.,Skaf, M.S.,Polikparpov, I.,Lima, M.C.,Galdino, S.L.,Brennan, R.G.,Baxter, J.D.,Pitta, I.R.,Webb, P.,Phillips, K.J.,Neves, F.A.
GQ-16, a novel peroxisome proliferator-activated receptor (PPAR gamma) ligand, promotes insulin sensitization without weight gain.
J.Biol.Chem., 287:28169-28179, 2012

PubMed Abstract: The recent discovery that peroxisome proliferator-activated receptor γ (PPARγ) targeted anti-diabetic drugs function by inhibiting Cdk5-mediated phosphorylation of the receptor has provided a new viewpoint to evaluate and perhaps develop improved insulin-sensitizing agents. Herein we report the development of a novel thiazolidinedione that retains similar anti-diabetic efficacy as rosiglitazone in mice yet does not elicit weight gain or edema, common side effects associated with full PPARγ activation. Further characterization of this compound shows GQ-16 to be an effective inhibitor of Cdk5-mediated phosphorylation of PPARγ. The structure of GQ-16 bound to PPARγ demonstrates that the compound utilizes a binding mode distinct from other reported PPARγ ligands, although it does share some structural features with other partial agonists, such as MRL-24 and PA-082, that have similarly been reported to dissociate insulin sensitization from weight gain. Hydrogen/deuterium exchange studies reveal that GQ-16 strongly stabilizes the β-sheet region of the receptor, presumably explaining the compound's efficacy in inhibiting Cdk5-mediated phosphorylation of Ser-273. Molecular dynamics simulations suggest that the partial agonist activity of GQ-16 results from the compound's weak ability to stabilize helix 12 in its active conformation. Our results suggest that the emerging model, whereby "ideal" PPARγ-based therapeutics stabilize the β-sheet/Ser-273 region and inhibit Cdk5-mediated phosphorylation while minimally invoking adipogenesis and classical agonism, is indeed a valid framework to develop improved PPARγ modulators that retain antidiabetic actions while minimizing untoward effects.

PubMed: 22584573
DOI: 10.1074/jbc.M111.332106

Experimental method

X-RAY DIFFRACTION (2.1 Å)