4ci4

From Proteopedia

(Difference between revisions)

Revision as of 12:19, 16 January 2019

Structural basis for GL479 a dual Peroxisome Proliferator-Activated Receptor alpha agonist

Structural highlights

4ci4 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:
Related:	4ci5
Activity:	Histone acetyltransferase, with EC number 2.3.1.48
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

Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-dependent transcription factors that control various functions in human organism, including the control of glucose and lipid metabolism. PPARgamma is a target of TZD agonists, clinically used to improve insulin sensitivity whereas fibrates, PPARalpha ligands, lower serum triglyceride levels. We report here the structural studies of GL479, a synthetic dual PPARalpha/gamma agonist, designed by a combination of clofibric acid skeleton and a phenyldiazenyl moiety, as bioisosteric replacement of stilbene group, in complex with both PPARalpha and PPARgamma receptors. GL479 was previously reported as a partial agonist of PPARgamma and a full agonist of PPARalpha with high affinity for both PPARs. Our structural studies reveal different binding modes of GL479 to PPARalpha and PPARgamma, which may explain the distinct activation behaviors observed for each receptor. In both cases the ligand interacts with a Tyr located at helix 12 (H12), resulting in the receptor active conformation. In the complex with PPARalpha, GL479 occupies the same region of the ligand-binding pocket (LBP) observed for other full agonists, whereas GL479 bound to PPARgamma displays a new binding mode. Our results indicate a novel region of PPARs LBP that may be explored for the design of partial agonists as well dual PPARalpha/gamma agonists that combine, simultaneously, the therapeutic effects of the treatment of insulin resistance and dyslipidemia.

Different binding and recognition modes of GL479, a dual agonist of Peroxisome Proliferator-Activated Receptor alpha/gamma.,Dos Santos JC, Bernardes A, Giampietro L, Ammazzalorso A, De Filippis B, Amoroso R, Polikarpov I J Struct Biol. 2015 Jul 14. pii: S1047-8477(15)30031-9. doi:, 10.1016/j.jsb.2015.07.006. PMID:26185032^[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
↑ Dos Santos JC, Bernardes A, Giampietro L, Ammazzalorso A, De Filippis B, Amoroso R, Polikarpov I. Different binding and recognition modes of GL479, a dual agonist of Peroxisome Proliferator-Activated Receptor alpha/gamma. J Struct Biol. 2015 Jul 14. pii: S1047-8477(15)30031-9. doi:, 10.1016/j.jsb.2015.07.006. PMID:26185032 doi:http://dx.doi.org/10.1016/j.jsb.2015.07.006

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/4ci4"

@@ Line 1: / Line 1: @@
 ==Structural basis for GL479 a dual Peroxisome Proliferator-Activated Receptor alpha agonist==
 <StructureSection load='4ci4' size='340' side='right' caption='[[4ci4]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4ci4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CI4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CI4 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4ci4]] 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=4CI4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CI4 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=Y1N:2-METHYL-2-[4-[2-[4-[(E)-PHENYLDIAZENYL]PHENOXY]ETHYL]PHENOXY]PROPANOIC+ACID'>Y1N</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ci5|4ci5]]</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] </span></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=4ci4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ci4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ci4 RCSB], [http://www.ebi.ac.uk/pdbsum/4ci4 PDBsum]</span></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=4ci4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ci4 OCA], [http://pdbe.org/4ci4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ci4 RCSB], [http://www.ebi.ac.uk/pdbsum/4ci4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ci4 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4ci4" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Peroxisome Proliferator-Activated Receptors|Peroxisome Proliferator-Activated Receptors]]
 == References ==
 <references/>
@@ Line 23: / Line 28: @@
 </StructureSection>
 [[Category: Histone acetyltransferase]]
+[[Category: Human]]
 [[Category: Bernardes, A]]
 [[Category: Polikarpov, I]]

4ci4

From Proteopedia

Revision as of 12:19, 16 January 2019

Structural basis for GL479 a dual Peroxisome Proliferator-Activated Receptor alpha agonist

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox