3pcu

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of human retinoic X receptor alpha ligand-binding domain complexed with LX0278 and SRC1 peptide

Structural highlights

3pcu 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 2Å
Ligands:
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]

Publication Abstract from PubMed

Glucose transporter 4 (GLUT4) is a principal glucose transporter in response to insulin, and impaired translocation or decreased expression of GLUT4 is believed to be one of the major pathological features of type 2 diabetes mellitus (T2DM). Therefore, induction of GLUT4 translocation or/and expression is a promising strategy for anti-T2DM drug discovery. Here we report that the natural product (+)-Rutamarin (Rut) functions as an efficient dual inducer on both insulin-induced GLUT4 translocation and expression. Rut-treated 3T3-L1 adipocytes exhibit efficiently enhanced insulin-induced glucose uptake, while diet-induced obese (DIO) mice based assays further confirm the Rut-induced improvement of glucose homeostasis and insulin sensitivity in vivo. Subsequent investigation of Rut acting targets indicates that as a specific protein tyrosine phosphatase 1B (PTP1B) inhibitor Rut induces basal GLUT4 translocation to some extent and largely enhances insulin-induced GLUT4 translocation through PI3 kinase-AKT/PKB pathway, while as an agonist of retinoid X receptor alpha (RXRalpha), Rut potently increases GLUT4 expression. Furthermore, by using molecular modeling and crystallographic approaches, the possible binding modes of Rut to these two targets have been also determined at atomic levels. All our results have thus highlighted the potential of Rut as both a valuable lead compound for anti-T2DM drug discovery and a promising chemical probe for GLUT4 associated pathways exploration.

(+)-Rutamarin as a dual inducer of Both GLUT4 translocation and expression efficiently ameliorates glucose homeostasis in insulin-resistant mice.,Zhang Y, Zhang H, Yao XG, Shen H, Chen J, Li C, Chen L, Zheng M, Ye J, Hu L, Shen X, Jiang H PLoS One. 2012;7(2):e31811. Epub 2012 Feb 27. PMID:22384078^[5]

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
↑ Zhang Y, Zhang H, Yao XG, Shen H, Chen J, Li C, Chen L, Zheng M, Ye J, Hu L, Shen X, Jiang H. (+)-Rutamarin as a dual inducer of Both GLUT4 translocation and expression efficiently ameliorates glucose homeostasis in insulin-resistant mice. PLoS One. 2012;7(2):e31811. Epub 2012 Feb 27. PMID:22384078 doi:10.1371/journal.pone.0031811

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/3pcu"

@@ Line 1: / Line 1: @@
-[[Image:3pcu.png|left|200px]]
-{{STRUCTURE_3pcu|  PDB=3pcu  |  SCENE=  }}
+==Crystal structure of human retinoic X receptor alpha ligand-binding domain complexed with LX0278 and SRC1 peptide==
+<StructureSection load='3pcu' size='340' side='right'caption='[[3pcu]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[3pcu]] 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=3PCU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3PCU FirstGlance]. <br>
+</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&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LX8:2-[(2S)-6-(2-METHYLBUT-3-EN-2-YL)-7-OXO-2,3-DIHYDRO-7H-FURO[3,2-G]CHROMEN-2-YL]PROPAN-2-YL+ACETATE'>LX8</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=3pcu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3pcu OCA], [https://pdbe.org/3pcu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3pcu RCSB], [https://www.ebi.ac.uk/pdbsum/3pcu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3pcu ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/RXRA_HUMAN 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.<ref>PMID:10195690</ref> <ref>PMID:11162439</ref> <ref>PMID:11915042</ref> <ref>PMID:20215566</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Glucose transporter 4 (GLUT4) is a principal glucose transporter in response to insulin, and impaired translocation or decreased expression of GLUT4 is believed to be one of the major pathological features of type 2 diabetes mellitus (T2DM). Therefore, induction of GLUT4 translocation or/and expression is a promising strategy for anti-T2DM drug discovery. Here we report that the natural product (+)-Rutamarin (Rut) functions as an efficient dual inducer on both insulin-induced GLUT4 translocation and expression. Rut-treated 3T3-L1 adipocytes exhibit efficiently enhanced insulin-induced glucose uptake, while diet-induced obese (DIO) mice based assays further confirm the Rut-induced improvement of glucose homeostasis and insulin sensitivity in vivo. Subsequent investigation of Rut acting targets indicates that as a specific protein tyrosine phosphatase 1B (PTP1B) inhibitor Rut induces basal GLUT4 translocation to some extent and largely enhances insulin-induced GLUT4 translocation through PI3 kinase-AKT/PKB pathway, while as an agonist of retinoid X receptor alpha (RXRalpha), Rut potently increases GLUT4 expression. Furthermore, by using molecular modeling and crystallographic approaches, the possible binding modes of Rut to these two targets have been also determined at atomic levels. All our results have thus highlighted the potential of Rut as both a valuable lead compound for anti-T2DM drug discovery and a promising chemical probe for GLUT4 associated pathways exploration.
-===Crystal structure of human retinoic X receptor alpha ligand-binding domain complexed with LX0278 and SRC1 peptide===
+(+)-Rutamarin as a dual inducer of Both GLUT4 translocation and expression efficiently ameliorates glucose homeostasis in insulin-resistant mice.,Zhang Y, Zhang H, Yao XG, Shen H, Chen J, Li C, Chen L, Zheng M, Ye J, Hu L, Shen X, Jiang H PLoS One. 2012;7(2):e31811. Epub 2012 Feb 27. PMID:22384078<ref>PMID:22384078</ref>
-{{ABSTRACT_PUBMED_22384078}}
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-==About this Structure==
+<div class="pdbe-citations 3pcu" style="background-color:#fffaf0;"></div>
-[[3pcu]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3PCU OCA].
 ==See Also==
-*[[Retinoid X receptor|Retinoid X receptor]]
+*[[Retinoid X receptor 3D structures|Retinoid X receptor 3D structures]]
+== References ==
-==Reference==
+<references/>
-<ref group="xtra">PMID:022384078</ref><references group="xtra"/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Chen, J.]]
+[[Category: Large Structures]]
-[[Category: Chen, L.]]
+[[Category: Chen J]]
-[[Category: Hu, L.]]
+[[Category: Chen L]]
-[[Category: Jiang, H.]]
+[[Category: Hu L]]
-[[Category: Li, C.]]
+[[Category: Jiang H]]
-[[Category: Shen, H.]]
+[[Category: Li C]]
-[[Category: Shen, X.]]
+[[Category: Shen H]]
-[[Category: Zhang, H.]]
+[[Category: Shen X]]
-[[Category: Zhang, Y.]]
+[[Category: Zhang H]]
-[[Category: Ligand-binding domain]]
+[[Category: Zhang Y]]
-[[Category: Nuclear receptor rxralpha]]
-[[Category: Transcription-transcription regulator complex]]

3pcu

From Proteopedia

Current revision

Crystal structure of human retinoic X receptor alpha ligand-binding domain complexed with LX0278 and SRC1 peptide

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