6c5t

From Proteopedia

(Difference between revisions)

Revision as of 10:26, 5 September 2018

PPARg LBD bound to SR11023

Structural highlights

6c5t is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
NonStd Res:
Gene:	PPARG, NR1C3 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[PPARG_HUMAN] Note=Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. Defects in PPARG may be associated with susceptibility to obesity (OBESITY) [MIM:601665]. It is a condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.^[1] Defects in PPARG are the cause of familial partial lipodystrophy type 3 (FPLD3) [MIM:604367]. Familial partial lipodystrophies (FPLD) are a heterogeneous group of genetic disorders characterized by marked loss of subcutaneous (sc) fat from the extremities. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia.^[2] ^[3] Genetic variations in PPARG can be associated with susceptibility to glioma type 1 (GLM1) [MIM:137800]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility.

Function

[PPARG_HUMAN] Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses.^[4] ^[5] ^[6]

Publication Abstract from PubMed

Peroxisome proliferator activated receptor gamma (PPARgamma) is a nuclear receptor and target for antidiabetics that increase insulin sensitivity. Owing to the side effects of PPARgamma full agonists, research has recently focused on non-activating ligands of PPARgamma, which increase insulin sensitivity with decreased side effects. Here, we present the crystal structures of inverse agonist SR10171 and a chemically related antagonist SR11023 bound to the PPARgamma ligand-binding domain, revealing an allosteric switch in the activation helix, helix 12 (H12), forming an antagonist conformation in the receptor. H12 interacts with the antagonists to become fixed in an alternative location. Native mass spectrometry indicates that this prevents contacts with coactivator peptides and allows binding of corepressor peptides. Antagonists of related nuclear receptors act to sterically prevent the active configuration of H12, whereas these antagonists of PPARgamma alternatively trap H12 in an inactive configuration, which we have termed the tumble and trap mechanism.

PPARgamma in Complex with an Antagonist and Inverse Agonist: a Tumble and Trap Mechanism of the Activation Helix.,Frkic RL, Marshall AC, Blayo AL, Pukala TL, Kamenecka TM, Griffin PR, Bruning JB iScience. 2018 Feb 27;5:69-79. doi: 10.1016/j.isci.2018.06.012. Epub 2018 Jul 2. PMID:30123887^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ristow M, Muller-Wieland D, Pfeiffer A, Krone W, Kahn CR. Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N Engl J Med. 1998 Oct 1;339(14):953-9. PMID:9753710 doi:10.1056/NEJM199810013391403
↑ Hegele RA, Cao H, Frankowski C, Mathews ST, Leff T. PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy. Diabetes. 2002 Dec;51(12):3586-90. PMID:12453919
↑ Agarwal AK, Garg A. A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab. 2002 Jan;87(1):408-11. PMID:11788685
↑ Mukherjee R, Jow L, Croston GE, Paterniti JR Jr. Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma2 versus PPARgamma1 and activation with retinoid X receptor agonists and antagonists. J Biol Chem. 1997 Mar 21;272(12):8071-6. PMID:9065481
↑ Yin Y, Yuan H, Wang C, Pattabiraman N, Rao M, Pestell RG, Glazer RI. 3-phosphoinositide-dependent protein kinase-1 activates the peroxisome proliferator-activated receptor-gamma and promotes adipocyte differentiation. Mol Endocrinol. 2006 Feb;20(2):268-78. Epub 2005 Sep 8. PMID:16150867 doi:10.1210/me.2005-0197
↑ Park SH, Choi HJ, Yang H, Do KH, Kim J, Lee DW, Moon Y. Endoplasmic reticulum stress-activated C/EBP homologous protein enhances nuclear factor-kappaB signals via repression of peroxisome proliferator-activated receptor gamma. J Biol Chem. 2010 Nov 12;285(46):35330-9. doi: 10.1074/jbc.M110.136259. Epub 2010, Sep 9. PMID:20829347 doi:10.1074/jbc.M110.136259
↑ Frkic RL, Marshall AC, Blayo AL, Pukala TL, Kamenecka TM, Griffin PR, Bruning JB. PPARgamma in Complex with an Antagonist and Inverse Agonist: a Tumble and Trap Mechanism of the Activation Helix. iScience. 2018 Feb 27;5:69-79. doi: 10.1016/j.isci.2018.06.012. Epub 2018 Jul 2. PMID:30123887 doi:http://dx.doi.org/10.1016/j.isci.2018.06.012

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6c5t"

@@ Line 3: / Line 3: @@
 <StructureSection load='6c5t' size='340' side='right' caption='[[6c5t]], [[Resolution|resolution]] 2.75&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6c5t]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6C5T OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6C5T FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6c5t]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6C5T OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6C5T FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EKP:2-{4-[(5-{[(1R)-1-(3-cyclopropylphenyl)ethyl]carbamoyl}-2,3-dimethyl-1H-indol-1-yl)methyl]phenyl}-2-methylpropanoic+acid'>EKP</scene></td></tr>
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PPARG, NR1C3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6c5t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6c5t OCA], [http://pdbe.org/6c5t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6c5t RCSB], [http://www.ebi.ac.uk/pdbsum/6c5t PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6c5t ProSAT]</span></td></tr>
 </table>
@@ Line 12: / Line 13: @@
 == Function ==
 [[http://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN]] Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses.<ref>PMID:9065481</ref> <ref>PMID:16150867</ref> <ref>PMID:20829347</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Peroxisome proliferator activated receptor gamma (PPARgamma) is a nuclear receptor and target for antidiabetics that increase insulin sensitivity. Owing to the side effects of PPARgamma full agonists, research has recently focused on non-activating ligands of PPARgamma, which increase insulin sensitivity with decreased side effects. Here, we present the crystal structures of inverse agonist SR10171 and a chemically related antagonist SR11023 bound to the PPARgamma ligand-binding domain, revealing an allosteric switch in the activation helix, helix 12 (H12), forming an antagonist conformation in the receptor. H12 interacts with the antagonists to become fixed in an alternative location. Native mass spectrometry indicates that this prevents contacts with coactivator peptides and allows binding of corepressor peptides. Antagonists of related nuclear receptors act to sterically prevent the active configuration of H12, whereas these antagonists of PPARgamma alternatively trap H12 in an inactive configuration, which we have termed the tumble and trap mechanism.
+PPARgamma in Complex with an Antagonist and Inverse Agonist: a Tumble and Trap Mechanism of the Activation Helix.,Frkic RL, Marshall AC, Blayo AL, Pukala TL, Kamenecka TM, Griffin PR, Bruning JB iScience. 2018 Feb 27;5:69-79. doi: 10.1016/j.isci.2018.06.012. Epub 2018 Jul 2. PMID:30123887<ref>PMID:30123887</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6c5t" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Peroxisome Proliferator-Activated Receptors|Peroxisome Proliferator-Activated Receptors]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Bruning, J B]]
 [[Category: Frkic, R L]]

6c5t

From Proteopedia

Revision as of 10:26, 5 September 2018

PPARg LBD bound to SR11023

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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