Partial Agonists Activate PPARgamma Using a Helix 12 Independent Mechanism

Journal Article · Thu May 28 04:00:00 EDT 2009 · Structure 15:1258,2007

OSTI ID:953505

Bruning, J B; Chalmers, M J; Prasad, S; Bushby, S A; Kamenecka, T A; He, Y; Nettles, K W; Griffin, P R

Binding to helix 12 of the ligand-binding domain of PPAR{gamma} 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 PPAR{gamma} 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 PPAR{gamma} 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.

• Research Organization: Stanford Linear Accelerator Center (SLAC)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC02-76SF00515
• OSTI ID: 953505
• Report Number(s): SLAC-REPRINT-2009-378
• Journal Information: Structure 15:1258,2007, Journal Name: Structure 15:1258,2007 Journal Issue: 10 Vol. 15
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
AMIDES
COMPLEXES
CRYSTAL STRUCTURE
DYNAMICS
FUNCTIONS
KINETICS
LIGANDS
Other
OTHER
STABILIZATION
SURFACES