PMID:17937915

Citation	Bruning, JB, Chalmers, MJ, Prasad, S, Busby, SA, Kamenecka, TM, He, Y, Nettles, KW and Griffin, PR (2007) Partial agonists activate PPARgamma using a helix 12 independent mechanism. Structure 15:1258-71
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.
Links	PubMed Online version:10.1016/j.str.2007.07.014
Keywords	Animals; Binding Sites; COS Cells; Cercopithecus aethiops; Deuterium Exchange Measurement; Ligands; Models, Molecular; PPAR gamma/agonists; PPAR gamma/chemistry; PPAR gamma/metabolism; Protein Structure, Tertiary
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:PPARG	enables	GO:0042802: identical protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:P37231-1	F		Seeded From UniProt	complete

References

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