2Q59

Crystal Structure of PPARgamma LBD bound to full agonist MRL20

Summary for 2Q59

• Entry DOI: 10.2210/pdb2q59/pdb
• Related: 2Q5P 2Q5S 2Q61 2Q6R 2Q6S
• Descriptor: Peroxisome Proliferator-Activated Receptor gamma, (2S)-2-(2-{[1-(4-METHOXYBENZOYL)-2-METHYL-5-(TRIFLUOROMETHOXY)-1H-INDOL-3-YL]METHYL}PHENOXY)PROPANOIC ACID, ... (4 entities in total)
• Functional Keywords: protein-ligand complex, ligand binding protein
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P37231 P37231
• Total number of polymer chains: 2
• Total formula weight: 63721.72

Authors

Bruning, J.B.,Nettles, K.W. (deposition date: 2007-05-31, release date: 2007-10-23, Last modification date: 2024-10-30)

Primary citation

Bruning, J.B.,Chalmers, M.J.,Prasad, S.,Busby, S.A.,Kamenecka, T.M.,He, Y.,Nettles, K.W.,Griffin, P.R.
Partial Agonists Activate PPARgamma Using a Helix 12 Independent Mechanism
Structure, 15:1258-1271, 2007

PubMed 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.

PubMed: 17937915
DOI: 10.1016/j.str.2007.07.014

Experimental method

X-RAY DIFFRACTION (2.2 Å)