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1rdt

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Revision as of 13:24, 16 December 2020

Crystal Structure of a new rexinoid bound to the RXRalpha ligand binding doamin in the RXRalpha/PPARgamma heterodimer

Structural highlights

1rdt is a 4 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:	1fm9, 1fm6
Gene:	RXRA, NR2B1 (HUMAN), PPARG, NR1C3 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[RXRA_HUMAN] Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes.^[1] ^[2] ^[3] ^[4] [PPAT_HUMAN] Dephosphorylates receptor tyrosine-protein kinase erbB-4 and inhibits the ligand-induced proteolytic cleavage.^[5]

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 tetrahydrobenzofuranyl and tetrahydrobenzothienyl propenoic acids that showed potent agonist activity against RXRalpha were synthesized via a structure-based design approach. Among the compounds studied, 46a,b showed not only very good potency against RXRalpha (K(i) = 6 nM) but was also found to be greater than 167-fold selective vs RARalpha (K(i) > 1000 nM). This compound profiled out as a full agonist in a cell-based transient transfection assay (EC(50) = 3 nM). The two antipodes were separated via chiral chromatography, and 46b was found to be 40-fold more potent than 46a. Interestingly, cocrystallization of 46a,b with the RXRalpha protein generated a liganded structure whereby the (S)-antipode was found in the binding pocket. Given orally in db/db mice or ZDF rats, 46a,b showed a significant glucose-lowering effect and an increase in liver mass. Triglycerides decreased significantly in db/db mice but increased in the ZDF rats. A dose-dependent decrease of nonesterified free fatty acids was seen in ZDF rats but not in db/db mice. These differences indicate a species specific effect of RXR agonists on lipid metabolism.

Structure-based design of potent retinoid X receptor alpha agonists.,Haffner CD, Lenhard JM, Miller AB, McDougald DL, Dwornik K, Ittoop OR, Gampe RT Jr, Xu HE, Blanchard S, Montana VG, Consler TG, Bledsoe RK, Ayscue A, Croom D J Med Chem. 2004 Apr 8;47(8):2010-29. PMID:15056000^[6]

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

References

↑ 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
↑ Harish S, Ashok MS, Khanam T, Rangarajan PN. Serine 27, a human retinoid X receptor alpha residue, phosphorylated by protein kinase A is essential for cyclicAMP-mediated downregulation of RXRalpha function. Biochem Biophys Res Commun. 2000 Dec 29;279(3):853-7. PMID:11162439 doi:10.1006/bbrc.2000.4043
↑ Tsutsumi T, Suzuki T, Shimoike T, Suzuki R, Moriya K, Shintani Y, Fujie H, Matsuura Y, Koike K, Miyamura T. Interaction of hepatitis C virus core protein with retinoid X receptor alpha modulates its transcriptional activity. Hepatology. 2002 Apr;35(4):937-46. PMID:11915042 doi:10.1053/jhep.2002.32470
↑ Santos NC, Kim KH. Activity of retinoic acid receptor-alpha is directly regulated at its protein kinase A sites in response to follicle-stimulating hormone signaling. Endocrinology. 2010 May;151(5):2361-72. doi: 10.1210/en.2009-1338. Epub 2010 Mar , 9. PMID:20215566 doi:10.1210/en.2009-1338
↑ Fleisig H, El-Din El-Husseini A, Vincent SR. Regulation of ErbB4 phosphorylation and cleavage by a novel histidine acid phosphatase. Neuroscience. 2004;127(1):91-100. PMID:15219672 doi:10.1016/j.neuroscience.2004.04.060
↑ Haffner CD, Lenhard JM, Miller AB, McDougald DL, Dwornik K, Ittoop OR, Gampe RT Jr, Xu HE, Blanchard S, Montana VG, Consler TG, Bledsoe RK, Ayscue A, Croom D. Structure-based design of potent retinoid X receptor alpha agonists. J Med Chem. 2004 Apr 8;47(8):2010-29. PMID:15056000 doi:http://dx.doi.org/10.1021/jm030565g

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/1rdt"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of a new rexinoid bound to the RXRalpha ligand binding doamin in the RXRalpha/PPARgamma heterodimer==
-<StructureSection load='1rdt' size='340' side='right' caption='[[1rdt]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
+<StructureSection load='1rdt' size='340' side='right'caption='[[1rdt]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1rdt]] is a 4 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=1RDT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1RDT FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1rdt]] is a 4 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=1RDT OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=1RDT FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=570:2-(2-BENZOYL-PHENYLAMINO)-3-{4-[2-(5-METHYL-2-PHENYL-OXAZOL-4-YL)-ETHOXY]-PHENYL}-PROPIONIC+ACID'>570</scene>, <scene name='pdbligand=L79:(S)-(2E)-3[4-(5,5,8,8-TETRAMETHYL-5,6,7,8-TETRAHYDRO-2-NAPHTHALENYL)TETRAHYDRO-1-BENZOFURAN-2-YL]-2-PROPENOIC+ACID'>L79</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=570:2-(2-BENZOYL-PHENYLAMINO)-3-{4-[2-(5-METHYL-2-PHENYL-OXAZOL-4-YL)-ETHOXY]-PHENYL}-PROPIONIC+ACID'>570</scene>, <scene name='pdbligand=L79:(S)-(2E)-3[4-(5,5,8,8-TETRAMETHYL-5,6,7,8-TETRAHYDRO-2-NAPHTHALENYL)TETRAHYDRO-1-BENZOFURAN-2-YL]-2-PROPENOIC+ACID'>L79</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1fm9|1fm9]], [[1fm6|1fm6]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1fm9|1fm9]], [[1fm6|1fm6]]</div></td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RXRA, NR2B1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), 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=1rdt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1rdt OCA], [http://pdbe.org/1rdt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1rdt RCSB], [http://www.ebi.ac.uk/pdbsum/1rdt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1rdt ProSAT]</span></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=1rdt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1rdt OCA], [http://pdbe.org/1rdt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1rdt RCSB], [http://www.ebi.ac.uk/pdbsum/1rdt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1rdt ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 32: / Line 32: @@
 ==See Also==
-*[[Peroxisome Proliferator-Activated Receptors|Peroxisome Proliferator-Activated Receptors]]
+*[[Peroxisome proliferator-activated receptor 3D structures|Peroxisome proliferator-activated receptor 3D structures]]
-*[[Retinoid X receptor|Retinoid X receptor]]
+*[[Retinoid X receptor 3D structures|Retinoid X receptor 3D structures]]
 == References ==
 <references/>
@@ Line 39: / Line 39: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Blanchard, S]]
 [[Category: Dwornik, K]]

1rdt

From Proteopedia

Revision as of 13:24, 16 December 2020

Crystal Structure of a new rexinoid bound to the RXRalpha ligand binding doamin in the RXRalpha/PPARgamma heterodimer

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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