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https://hdl.handle.net/2440/75299
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Type: | Journal article |
Title: | Partial agonists activate PPARγ using a helix 12 independent mechanism |
Other Titles: | Partial agonists activate PPARgamma using a helix 12 independent mechanism |
Author: | Bruning, J. Chalmers, M. Prasad, S. Busby, S. Kamenecka, T. He, Y. Nettles, K. Griffin, P. |
Citation: | Structure, 2007; 15(10):1258-1271 |
Publisher: | Cell Press |
Issue Date: | 2007 |
ISSN: | 0969-2126 1878-4186 |
Statement of Responsibility: | John B. Bruning, Michael J. Chalmers, Swati Prasad, Scott A. Busby, Theodore M. Kamenecka, Yuanjun He, Kendall W. Nettles, and Patrick R. Griffin |
Abstract: | Binding to helix 12 of the ligand-binding domain of PPARgamma is required for full agonist activity. Previously, the degree of stabilization of the activation function 2 (AF-2) surface was thought to correlate with the degree of agonism and transactivation. To examine this mechanism, we probed structural dynamics of PPARgamma with agonists that induced graded transcriptional responses. Here we present crystal structures and amide H/D exchange (HDX) kinetics for six of these complexes. Amide HDX revealed each ligand induced unique changes to the dynamics of the ligand-binding domain (LBD). Full agonists stabilized helix 12, whereas intermediate and partial agonists did not at all, and rather differentially stabilized other regions of the binding pocket. The gradient of PPARgamma transactivation cannot be accounted for solely through changes to the dynamics of AF-2. Thus, our understanding of allosteric signaling must be extended beyond the idea of a dynamic helix 12 acting as a molecular switch. |
Keywords: | COS Cells Animals PPAR gamma Ligands Deuterium Exchange Measurement Binding Sites Protein Structure, Tertiary Models, Molecular Chlorocebus aethiops |
Rights: | © 2007 Elsevier Ltd. All rights reserved |
DOI: | 10.1016/j.str.2007.07.014 |
Published version: | http://dx.doi.org/10.1016/j.str.2007.07.014 |
Appears in Collections: | Aurora harvest 4 Molecular and Biomedical Science publications |
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