Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/119018
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Type: Journal article
Title: Chemical crosslinking mass spectrometry reveals the conformational landscape of the activation helix of PPARγ; a model for ligand-dependent antagonism
Other Titles: Chemical crosslinking mass spectrometry reveals the conformational landscape of the activation helix of PPARgamma; a model for ligand-dependent antagonism
Author: Zheng, J.
Corzo, C.
Chang, M.
Shang, J.
Lam, V.
Brust, R.
Blayo, A.
Bruning, J.
Kamenecka, T.
Kojetin, D.
Griffin, P.
Citation: Structure, 2018; 26(11):1431-1439
Publisher: Elsevier
Issue Date: 2018
ISSN: 0969-2126
1878-4186
Statement of
Responsibility: 
Jie Zheng, Cesar Corzo, Mi Ra Chang, Jinsai Shang, Vinh Q. Lam, Richard Brust, Anne-Laure Blayo, John B. Bruning, Theodore M. Kamenecka, Douglas J. Kojetin and Patrick R. Griffin
Abstract: Peroxisome proliferator-activated receptors (PPARs) are pharmacological targets for the treatment of metabolic disorders. Previously, we demonstrated the anti-diabetic effects of SR1664, a PPARγ modulator lacking classical transcriptional agonism, despite its poor pharmacokinetic properties. Here, we report identification of the antagonist SR11023 as a potent insulin sensitizer with significant plasma exposure following oral administration. To determine the structural mechanism of ligand-dependent antagonism of PPARγ, we employed an integrated approach combining solution-phase biophysical techniques to monitor activation helix (helix 12) conformational dynamics. While informative on receptor dynamics, hydrogen/deuterium exchange mass spectrometry and nuclear magnetic resonance data provide limited information regarding the specific orientations of structural elements. In contrast, label-free quantitative crosslinking mass spectrometry revealed that binding of SR11023 to PPARγ enhances interaction with co-repressor motifs by pushing H12 away from the agonist active conformation toward the H2-H3 loop region (i.e., the omega loop), revealing the molecular mechanism for active antagonism of PPARγ.
Keywords: Cross-linking mass spectrometry; XL-MS; HDX-MS; hydrogen-deuterium exchange; NMR; nuclear receptors; PPARγ; activation function 2; AF-2; antagonist
Rights: © 2018 Elsevier Ltd.
DOI: 10.1016/j.str.2018.07.007
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