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6kay

From Proteopedia

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Current revision

X-ray structure of human PPARalpha ligand binding domain-GW7647 co-crystals obtained by soaking

Structural highlights

6kay is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.735Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PPARA_HUMAN Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety (By similarity). Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Most triacylglycerol-lowering fibrates have been developed in the 1960s-1980s before their molecular target, peroxisome proliferator-activated receptor alpha (PPARalpha), was identified. Twenty-one ligand-bound PPARalpha structures have been deposited in the Protein Data Bank since 2001; however, binding modes of fibrates and physiological ligands remain unknown. Here we show thirty-four X-ray crystallographic structures of the PPARalpha ligand-binding domain, which are composed of a "Center" and four "Arm" regions, in complexes with five endogenous fatty acids, six fibrates in clinical use, and six synthetic PPARalpha agonists. High-resolution structural analyses, in combination with coactivator recruitment and thermostability assays, demonstrate that stearic and palmitic acids are presumably physiological ligands; coordination to Arm III is important for high PPARalpha potency/selectivity of pemafibrate and GW7647; and agonistic activities of four fibrates are enhanced by the partial agonist GW9662. These results renew our understanding of PPARalpha ligand recognition and contribute to the molecular design of next-generation PPAR-targeted drugs.

PPARalpha Ligand-Binding Domain Structures with Endogenous Fatty Acids and Fibrates.,Kamata S, Oyama T, Saito K, Honda A, Yamamoto Y, Suda K, Ishikawa R, Itoh T, Watanabe Y, Shibata T, Uchida K, Suematsu M, Ishii I iScience. 2020 Oct 23;23(11):101727. doi: 10.1016/j.isci.2020.101727. eCollection, 2020 Nov 20. PMID:33205029^[5]

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

References

↑ Sher T, Yi HF, McBride OW, Gonzalez FJ. cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor. Biochemistry. 1993 Jun 1;32(21):5598-604. PMID:7684926
↑ Juge-Aubry CE, Gorla-Bajszczak A, Pernin A, Lemberger T, Wahli W, Burger AG, Meier CA. Peroxisome proliferator-activated receptor mediates cross-talk with thyroid hormone receptor by competition for retinoid X receptor. Possible role of a leucine zipper-like heptad repeat. J Biol Chem. 1995 Jul 28;270(30):18117-22. PMID:7629123
↑ Yan ZH, Karam WG, Staudinger JL, Medvedev A, Ghanayem BI, Jetten AM. Regulation of peroxisome proliferator-activated receptor alpha-induced transactivation by the nuclear orphan receptor TAK1/TR4. J Biol Chem. 1998 May 1;273(18):10948-57. PMID:9556573
↑ Gorla-Bajszczak A, Juge-Aubry C, Pernin A, Burger AG, Meier CA. Conserved amino acids in the ligand-binding and tau(i) domains of the peroxisome proliferator-activated receptor alpha are necessary for heterodimerization with RXR. Mol Cell Endocrinol. 1999 Jan 25;147(1-2):37-47. PMID:10195690
↑ Kamata S, Oyama T, Saito K, Honda A, Yamamoto Y, Suda K, Ishikawa R, Itoh T, Watanabe Y, Shibata T, Uchida K, Suematsu M, Ishii I. PPARalpha Ligand-Binding Domain Structures with Endogenous Fatty Acids and Fibrates. iScience. 2020 Oct 23;23(11):101727. doi: 10.1016/j.isci.2020.101727. eCollection, 2020 Nov 20. PMID:33205029 doi:http://dx.doi.org/10.1016/j.isci.2020.101727

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 3: / Line 3: @@
 <StructureSection load='6kay' size='340' side='right'caption='[[6kay]], [[Resolution|resolution]] 1.73&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6kay]] 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=6KAY OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6KAY FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6kay]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KAY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6KAY FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2VN:2-[(4-{2-[(4-cyclohexylbutyl)(cyclohexylcarbamoyl)amino]ethyl}phenyl)sulfanyl]-2-methylpropanoic+acid'>2VN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.735&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PPARA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2VN:2-[(4-{2-[(4-cyclohexylbutyl)(cyclohexylcarbamoyl)amino]ethyl}phenyl)sulfanyl]-2-methylpropanoic+acid'>2VN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6kay FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kay OCA], [http://pdbe.org/6kay PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6kay RCSB], [http://www.ebi.ac.uk/pdbsum/6kay PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6kay ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6kay FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kay OCA], [https://pdbe.org/6kay PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6kay RCSB], [https://www.ebi.ac.uk/pdbsum/6kay PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6kay ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/PPARA_HUMAN PPARA_HUMAN]] Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety (By similarity). Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2.<ref>PMID:7684926</ref> <ref>PMID:7629123</ref> <ref>PMID:9556573</ref> <ref>PMID:10195690</ref>
+[https://www.uniprot.org/uniprot/PPARA_HUMAN PPARA_HUMAN] Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety (By similarity). Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2.<ref>PMID:7684926</ref> <ref>PMID:7629123</ref> <ref>PMID:9556573</ref> <ref>PMID:10195690</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 6kay" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Peroxisome proliferator-activated receptor 3D structures|Peroxisome proliferator-activated receptor 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Ishii, I]]
+[[Category: Ishii I]]
-[[Category: Kamata, S]]
+[[Category: Kamata S]]
-[[Category: Oyama, T]]
+[[Category: Oyama T]]
-[[Category: Saito, K]]
+[[Category: Saito K]]
-[[Category: Suda, K]]
+[[Category: Suda K]]
-[[Category: Nuclear receptor]]
-[[Category: Ppar]]
-[[Category: Protein-ligand complex]]
-[[Category: Transcription]]

6kay

From Proteopedia

Current revision

X-ray structure of human PPARalpha ligand binding domain-GW7647 co-crystals obtained by soaking

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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