2q5p: Difference between revisions

Revision as of 14:24, 4 May 2008

Crystal Structure of PPARgamma bound to partial agonist MRL24

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.

About this StructureAbout this Structure

2Q5P is a Single protein structure of sequence from Homo sapiens. 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 Sun May 4 14:24:18 2008

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OCA

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 [[Image:2q5p.jpg|left|200px]]
- {{Structure
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-|GENE= PPARG, NR1C3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
+-->
-|DOMAIN=
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-|RELATEDENTRY=[[2q59|2Q59]], [[2q5s|2Q5S]], [[2q61|2Q61]], [[2q6r|2Q6R]], [[2q6s|2Q6S]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2q5p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q5p OCA], [http://www.ebi.ac.uk/pdbsum/2q5p PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2q5p RCSB]</span>
-}}
 '''Crystal Structure of PPARgamma bound to partial agonist MRL24'''
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 [[Category: Bruning, J B.]]
 [[Category: Nettles, K W.]]
-[[Category: ligand binding protein]]
+[[Category: Ligand binding protein]]
-[[Category: protein-ligand complex]]
+[[Category: Protein-ligand complex]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 14:24:18 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:45:05 2008''