2j14: Difference between revisions

Latest revision as of 14:31, 13 December 2023

3,4,5-Trisubstituted Isoxazoles as Novel PPARdelta Agonists: Part2

Structural highlights

2j14 is a 2 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 2.8Å
Ligands:	GNI
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PPARD_HUMAN Ligand-activated transcription factor. Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-linoleic acid and eicosapentanoic acid. Once activated by a ligand, the receptor binds to promoter elements of target genes. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the acyl-CoA oxidase gene. Decreases expression of NPC1L1 once activated by a ligand.^[1] ^[2]

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

A series of PPARdelta-selective agonists was investigated and optimized for a favorable in vivo pharmacokinetic profile. Isoxazole LCI765 (17d) was found to be a potent and selective PPARdelta agonist with good in vivo PK properties in mouse (C(max)=5.1 microM, t(1/2)=3.1 h). LCI765 regulated expression of genes involved in energy homeostasis in relevant tissues when dosed orally in C57BL6 mice. A co-crystal structure of compound LCI765 and the LBD of PPARdelta is discussed.

3,4,5-Trisubstituted isoxazoles as novel PPARdelta agonists. Part 2.,Epple R, Azimioara M, Russo R, Xie Y, Wang X, Cow C, Wityak J, Karanewsky D, Bursulaya B, Kreusch A, Tuntland T, Gerken A, Iskandar M, Saez E, Martin Seidel H, Tian SS Bioorg Med Chem Lett. 2006 Nov 1;16(21):5488-92. Epub 2006 Aug 22. PMID:16931011^[3]

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

References

↑ Schmidt A, Endo N, Rutledge SJ, Vogel R, Shinar D, Rodan GA. Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids. Mol Endocrinol. 1992 Oct;6(10):1634-41. PMID:1333051 doi:https://dx.doi.org/10.1210/mend.6.10.1333051
↑ van der Veen JN, Kruit JK, Havinga R, Baller JF, Chimini G, Lestavel S, Staels B, Groot PH, Groen AK, Kuipers F. Reduced cholesterol absorption upon PPARdelta activation coincides with decreased intestinal expression of NPC1L1. J Lipid Res. 2005 Mar;46(3):526-34. Epub 2004 Dec 16. PMID:15604518 doi:https://dx.doi.org/10.1194/jlr.M400400-JLR200
↑ Epple R, Azimioara M, Russo R, Xie Y, Wang X, Cow C, Wityak J, Karanewsky D, Bursulaya B, Kreusch A, Tuntland T, Gerken A, Iskandar M, Saez E, Martin Seidel H, Tian SS. 3,4,5-Trisubstituted isoxazoles as novel PPARdelta agonists. Part 2. Bioorg Med Chem Lett. 2006 Nov 1;16(21):5488-92. Epub 2006 Aug 22. PMID:16931011 doi:10.1016/j.bmcl.2006.08.052

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Schmidt A, Endo N, Rutledge SJ, Vogel R, Shinar D, Rodan GA. Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids. Mol Endocrinol. 1992 Oct;6(10):1634-41. PMID:1333051 doi:https://dx.doi.org/10.1210/mend.6.10.1333051

[2] van der Veen JN, Kruit JK, Havinga R, Baller JF, Chimini G, Lestavel S, Staels B, Groot PH, Groen AK, Kuipers F. Reduced cholesterol absorption upon PPARdelta activation coincides with decreased intestinal expression of NPC1L1. J Lipid Res. 2005 Mar;46(3):526-34. Epub 2004 Dec 16. PMID:15604518 doi:https://dx.doi.org/10.1194/jlr.M400400-JLR200

[3] Epple R, Azimioara M, Russo R, Xie Y, Wang X, Cow C, Wityak J, Karanewsky D, Bursulaya B, Kreusch A, Tuntland T, Gerken A, Iskandar M, Saez E, Martin Seidel H, Tian SS. 3,4,5-Trisubstituted isoxazoles as novel PPARdelta agonists. Part 2. Bioorg Med Chem Lett. 2006 Nov 1;16(21):5488-92. Epub 2006 Aug 22. PMID:16931011 doi:10.1016/j.bmcl.2006.08.052

[1]

[2]

[3]

@@ Line 3: / Line 3: @@
 <StructureSection load='2j14' size='340' side='right'caption='[[2j14]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2j14]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2J14 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2J14 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2j14]] is a 2 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=2J14 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2J14 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GNI:(3-{4-[2-(2,4-DICHLORO-PHENOXY)-ETHYLCARBAMOYL]-5-PHENYL-ISOXAZOL-3-YL}-PHENYL)-ACETIC+ACID'>GNI</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]] 2.8&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1gwx|1gwx]], [[1y0s|1y0s]], [[2awh|2awh]], [[2b50|2b50]], [[2baw|2baw]], [[2gwx|2gwx]], [[3gwx|3gwx]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GNI:(3-{4-[2-(2,4-DICHLORO-PHENOXY)-ETHYLCARBAMOYL]-5-PHENYL-ISOXAZOL-3-YL}-PHENYL)-ACETIC+ACID'>GNI</scene></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=2j14 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2j14 OCA], [https://pdbe.org/2j14 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2j14 RCSB], [https://www.ebi.ac.uk/pdbsum/2j14 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2j14 ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/PPARD_HUMAN PPARD_HUMAN] Ligand-activated transcription factor. Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-linoleic acid and eicosapentanoic acid. Once activated by a ligand, the receptor binds to promoter elements of target genes. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the acyl-CoA oxidase gene. Decreases expression of NPC1L1 once activated by a ligand.<ref>PMID:1333051</ref> <ref>PMID:15604518</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 34: / Line 36: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Azimioara, M]]
+[[Category: Azimioara M]]
-[[Category: Bursulaya, B]]
+[[Category: Bursulaya B]]
-[[Category: Cow, C]]
+[[Category: Cow C]]
-[[Category: Epple, R]]
+[[Category: Epple R]]
-[[Category: Gerken, A]]
+[[Category: Gerken A]]
-[[Category: Iskandar, M]]
+[[Category: Iskandar M]]
-[[Category: Karanewsky, D]]
+[[Category: Karanewsky D]]
-[[Category: Kreusch, A]]
+[[Category: Kreusch A]]
-[[Category: Russo, R]]
+[[Category: Russo R]]
-[[Category: Saez, E]]
+[[Category: Saez E]]
-[[Category: Seidel, H M]]
+[[Category: Seidel HM]]
-[[Category: Tian, S S]]
+[[Category: Tian SS]]
-[[Category: Tuntland, T]]
+[[Category: Tuntland T]]
-[[Category: Wang, X]]
+[[Category: Wang X]]
-[[Category: Wityak, J]]
+[[Category: Wityak J]]
-[[Category: Xie, Y]]
+[[Category: Xie Y]]
-[[Category: Activator]]
-[[Category: Alternative splicing]]
-[[Category: Dna-binding]]
-[[Category: Fatty acid]]
-[[Category: Metal-binding]]
-[[Category: Nuclear protein]]
-[[Category: Nuclear receptor fold]]
-[[Category: Ppar]]
-[[Category: Receptor]]
-[[Category: Transcription]]
-[[Category: Transcription regulation]]
-[[Category: Zinc]]
-[[Category: Zinc-finger]]

2j14: Difference between revisions

Latest revision as of 14:31, 13 December 2023

3,4,5-Trisubstituted Isoxazoles as Novel PPARdelta Agonists: Part2

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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