2q61
From Proteopedia
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|PDB= 2q61 |SIZE=350|CAPTION= <scene name='initialview01'>2q61</scene>, resolution 2.197Å | |PDB= 2q61 |SIZE=350|CAPTION= <scene name='initialview01'>2q61</scene>, resolution 2.197Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=SF1:1-BENZYL-5-CHLORO-3-(PHENYLTHIO)-1H-INDOLE-2-CARBOXYLIC ACID'>SF1</scene> | + | |LIGAND= <scene name='pdbligand=SF1:1-BENZYL-5-CHLORO-3-(PHENYLTHIO)-1H-INDOLE-2-CARBOXYLIC+ACID'>SF1</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= PPARG, NR1C3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= PPARG, NR1C3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[2q59|2Q59]], [[2q5p|2Q5P]], [[2q5s|2Q5S]], [[2q6r|2Q6R]], [[2q6s|2Q6S]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2q61 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q61 OCA], [http://www.ebi.ac.uk/pdbsum/2q61 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2q61 RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
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. | 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. | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Diabetes mellitus, insulin-resistant, with acanthosis nigricans and hypertension OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Glioblastoma, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Insulin resistance, severe, digenic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Lipodystrophy, familial partial OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Obesity, resistance to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Obesity, severe OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Bruning, J B.]] | [[Category: Bruning, J B.]] | ||
[[Category: Nettles, K W.]] | [[Category: Nettles, K W.]] | ||
| - | [[Category: SF1]] | ||
[[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 | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:45:11 2008'' |
Revision as of 01:45, 31 March 2008
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| , resolution 2.197Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Gene: | PPARG, NR1C3 (Homo sapiens) | ||||||
| Related: | 2Q59, 2Q5P, 2Q5S, 2Q6R, 2Q6S
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal Structure of PPARgamma ligand binding domain bound to partial agonist SR145
Overview
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 Structure
2Q61 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
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 Mar 31 04:45:11 2008
