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1kkq

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Crystal structure of the human PPAR-alpha ligand-binding domain in complex with an antagonist GW6471 and a SMRT corepressor motif

Structural highlights

1kkq is a 8 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 3Å
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]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Repression of gene transcription by nuclear receptors is mediated by interactions with co-repressor proteins such as SMRT and N-CoR, which in turn recruit histone deacetylases to the chromatin. Aberrant interactions between nuclear receptors and co-repressors contribute towards acute promyelocytic leukaemia and thyroid hormone resistance syndrome. The binding of co-repressors to nuclear receptors occurs in the unliganded state, and can be stabilized by antagonists. Here we report the crystal structure of a ternary complex containing the peroxisome proliferator-activated receptor-alpha ligand-binding domain bound to the antagonist GW6471 and a SMRT co-repressor motif. In this structure, the co-repressor motif adopts a three-turn alpha-helix that prevents the carboxy-terminal activation helix (AF-2) of the receptor from assuming the active conformation. Binding of the co-repressor motif is further reinforced by the antagonist, which blocks the AF-2 helix from adopting the active position. Biochemical analyses and structure-based mutagenesis indicate that this mode of co-repressor binding is highly conserved across nuclear receptors.

Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha.,Xu HE, Stanley TB, Montana VG, Lambert MH, Shearer BG, Cobb JE, McKee DD, Galardi CM, Plunket KD, Nolte RT, Parks DJ, Moore JT, Kliewer SA, Willson TM, Stimmel JB Nature. 2002 Feb 14;415(6873):813-7. PMID:11845213^[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
↑ Xu HE, Stanley TB, Montana VG, Lambert MH, Shearer BG, Cobb JE, McKee DD, Galardi CM, Plunket KD, Nolte RT, Parks DJ, Moore JT, Kliewer SA, Willson TM, Stimmel JB. Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha. Nature. 2002 Feb 14;415(6873):813-7. PMID:11845213 doi:10.1038/415813a

1 Structural highlights
2 Function
3 Evolutionary Conservation
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/1kkq"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the human PPAR-alpha ligand-binding domain in complex with an antagonist GW6471 and a SMRT corepressor motif==
-<StructureSection load='1kkq' size='340' side='right' caption='[[1kkq]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
+<StructureSection load='1kkq' size='340' side='right'caption='[[1kkq]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1kkq]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1KKQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1KKQ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1kkq]] is a 8 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=1KKQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1KKQ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=471:N-((2S)-2-({(1Z)-1-METHYL-3-OXO-3-[4-(TRIFLUOROMETHYL)+PHENYL]PROP-1-ENYL}AMINO)-3-{4-[2-(5-METHYL-2-PHENYL-1,3-OXAZOL-4-YL)ETHOXY]PHENYL}PROPYL)PROPANAMIDE'>471</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]] 3&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1k7l|1k7l]], [[1k74|1k74]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=471:N-((2S)-2-({(1Z)-1-METHYL-3-OXO-3-[4-(TRIFLUOROMETHYL)+PHENYL]PROP-1-ENYL}AMINO)-3-{4-[2-(5-METHYL-2-PHENYL-1,3-OXAZOL-4-YL)ETHOXY]PHENYL}PROPYL)PROPANAMIDE'>471</scene></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=1kkq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1kkq OCA], [http://pdbe.org/1kkq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1kkq RCSB], [http://www.ebi.ac.uk/pdbsum/1kkq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1kkq 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=1kkq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1kkq OCA], [https://pdbe.org/1kkq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1kkq RCSB], [https://www.ebi.ac.uk/pdbsum/1kkq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1kkq ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/NCOR2_HUMAN NCOR2_HUMAN]] Transcriptional corepressor of NR4A2/NURR1 and acts through histone deacetylases (HDACs) to keep promoters of NR4A2/NURR1 target genes in a repressed deacetylated state (By similarity). Mediates the transcriptional repression activity of some nuclear receptors by promoting chromatin condensation, thus preventing access of the basal transcription. Isoform 1 and isoform 5 have different affinities for different nuclear receptors.
+[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>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/kk/1kkq_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/kk/1kkq_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
@@ Line 29: / Line 29: @@
 </div>
 <div class="pdbe-citations 1kkq" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Nuclear receptor corepressor|Nuclear receptor corepressor]]
+*[[Peroxisome Proliferator-Activated Receptors|Peroxisome Proliferator-Activated Receptors]]
+*[[Peroxisome proliferator-activated receptor 3D structures|Peroxisome proliferator-activated receptor 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Cobb, J E]]
+[[Category: Homo sapiens]]
-[[Category: Galardi, C M]]
+[[Category: Large Structures]]
-[[Category: Lambert, M H]]
+[[Category: Cobb JE]]
-[[Category: McKee, D D]]
+[[Category: Galardi CM]]
-[[Category: Montana, V G]]
+[[Category: Lambert MH]]
-[[Category: Nolte, R T]]
+[[Category: McKee DD]]
-[[Category: Parks, D J]]
+[[Category: Montana VG]]
-[[Category: Shearer, B G]]
+[[Category: Nolte RT]]
-[[Category: Stanley, T B]]
+[[Category: Parks DJ]]
-[[Category: Xu, H E]]
+[[Category: Shearer BG]]
-[[Category: Nuclear corepressor nuclear hormone receptors antagonist]]
+[[Category: Stanley TB]]
-[[Category: Transcription]]
+[[Category: Xu HE]]

1kkq

From Proteopedia

Current revision

Crystal structure of the human PPAR-alpha ligand-binding domain in complex with an antagonist GW6471 and a SMRT corepressor motif

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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