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4n5g

From Proteopedia

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Current revision

Crystal Structure of RXRa LBD complexed with a synthetic modulator K8012

Structural highlights

4n5g is a 4 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 2.11Å
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

Retinoid X receptor-alpha (RXRalpha), an intriguing and unique drug target, can serve as an intracellular target mediating the anticancer effects of certain nonsteroidal anti-inflammatory drugs (NSAIDs), including sulindac. We report the synthesis and characterization of two sulindac analogs, K-8008 and K-8012, which exert improved anticancer activities over sulindac in a RXRalpha-dependent manner. The analogs inhibit the interaction of the N-terminally truncated RXRalpha (tRXRalpha) with the p85alpha subunit of PI3K, leading to suppression of AKT activation and induction of apoptosis. Crystal structures of the RXRalpha ligand-binding domain (LBD) with K-8008 or K-8012 reveal that both compounds bind to tetrameric RXRalpha LBD at a site different from the classical ligand-binding pocket. Thus, these results identify K-8008 and K-8012 as tRXRalpha modulators and define a binding mechanism for regulating the nongenomic action of tRXRalpha.

Sulindac-Derived RXRalpha Modulators Inhibit Cancer Cell Growth by Binding to a Novel Site.,Chen L, Wang ZG, Aleshin AE, Chen F, Chen J, Jiang F, Alitongbieke G, Zeng Z, Ma Y, Huang M, Zhou H, Cadwell G, Zheng JF, Huang PQ, Liddington RC, Zhang XK, Su Y Chem Biol. 2014 Apr 2. pii: S1074-5521(14)00077-5. doi:, 10.1016/j.chembiol.2014.02.017. PMID:24704507^[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
↑ Chen L, Wang ZG, Aleshin AE, Chen F, Chen J, Jiang F, Alitongbieke G, Zeng Z, Ma Y, Huang M, Zhou H, Cadwell G, Zheng JF, Huang PQ, Liddington RC, Zhang XK, Su Y. Sulindac-Derived RXRalpha Modulators Inhibit Cancer Cell Growth by Binding to a Novel Site. Chem Biol. 2014 Apr 2. pii: S1074-5521(14)00077-5. doi:, 10.1016/j.chembiol.2014.02.017. PMID:24704507 doi:http://dx.doi.org/10.1016/j.chembiol.2014.02.017

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/4n5g"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4n5g]] is a 4 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=4N5G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4N5G FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K09:5-(2-{(1Z)-5-FLUORO-2-METHYL-1-[4-(PROPAN-2-YL)BENZYLIDENE]-1H-INDEN-3-YL}ETHYL)-1H-TETRAZOLE'>K09</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]] 2.11&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K09:5-(2-{(1Z)-5-FLUORO-2-METHYL-1-[4-(PROPAN-2-YL)BENZYLIDENE]-1H-INDEN-3-YL}ETHYL)-1H-TETRAZOLE'>K09</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=4n5g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4n5g OCA], [https://pdbe.org/4n5g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4n5g RCSB], [https://www.ebi.ac.uk/pdbsum/4n5g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4n5g ProSAT]</span></td></tr>
 </table>

4n5g

From Proteopedia

Current revision

Crystal Structure of RXRa LBD complexed with a synthetic modulator K8012

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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