2q61
Crystal Structure of PPARgamma ligand binding domain bound to partial agonist SR145
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OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[601487], Diabetes mellitus, insulin-resistant, with acanthosis nigricans and hypertension OMIM:[601487], Glioblastoma, susceptibility to OMIM:[601487], Insulin resistance, severe, digenic OMIM:[601487], Lipodystrophy, familial partial OMIM:[601487], Obesity, resistance to OMIM:[601487], Obesity, severe OMIM:[601487]
About this StructureAbout this Structure
2Q61 is a Single protein structure of sequence from Homo sapiens with SF1 as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Partial Agonists Activate PPARgamma Using a Helix 12 Independent Mechanism., Bruning JB, Chalmers MJ, Prasad S, Busby SA, Kamenecka TM, He Y, Nettles KW, Griffin PR, Structure. 2007 Oct;15(10):1258-71. PMID:17937915
Page seeded by OCA on Mon Nov 12 23:30:02 2007