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2Q6R

Crystal structure of PPAR gamma complexed with partial agonist SF147

Summary for 2Q6R
Entry DOI10.2210/pdb2q6r/pdb
Related2Q59 2Q5P 2Q5S 2Q61 2Q6S
DescriptorPeroxisome Proliferator-Activated Receptor gamma, 5-CHLORO-1-(3-METHOXYBENZYL)-3-(PHENYLTHIO)-1H-INDOLE-2-CARBOXYLIC ACID (3 entities in total)
Functional Keywordsprotein-ligand complex, ligand binding protein
Biological sourceHomo sapiens (human)
Cellular locationNucleus: P37231
Total number of polymer chains2
Total formula weight63438.45
Authors
Bruning, J.B.,Nettles, K.W. (deposition date: 2007-06-01, release date: 2007-10-23, Last modification date: 2023-08-30)
Primary citationBruning, 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
Cited by
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
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.407 Å)
Structure validation

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