4dqm

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{{STRUCTURE_4dqm| PDB=4dqm | SCENE= }}
 
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===Revealing a marine natural product as a novel agonist for retinoic acid receptors with a unique binding mode and antitumor activity===
 
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{{ABSTRACT_PUBMED_22642567}}
 
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==Disease==
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==Revealing a marine natural product as a novel agonist for retinoic acid receptors with a unique binding mode and antitumor activity==
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[[http://www.uniprot.org/uniprot/RARA_HUMAN RARA_HUMAN]] Note=Chromosomal aberrations involving RARA are commonly found in acute promyelocytic leukemia. Translocation t(11;17)(q32;q21) with ZBTB16/PLZF; translocation t(15;17)(q21;q21) with PML; translocation t(5;17)(q32;q11) with NPM. The PML-RARA oncoprotein requires both the PML ring structure and coiled-coil domain for both interaction with UBE2I, nuclear microspeckle location and sumoylation. In addition, the coiled-coil domain functions in blocking RA-mediated transactivation and cell differentiation. [[http://www.uniprot.org/uniprot/NCOA1_HUMAN NCOA1_HUMAN]] Note=A chromosomal aberration involving NCOA1 is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with PAX3 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. Rhabdomyosarcoma is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children.
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<StructureSection load='4dqm' size='340' side='right'caption='[[4dqm]], [[Resolution|resolution]] 2.75&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4dqm]] 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=4DQM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DQM FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.75&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LUF:(5S)-4-[(3E,7E)-4,8-DIMETHYL-10-(2,6,6-TRIMETHYLCYCLOHEX-1-EN-1-YL)DECA-3,7-DIEN-1-YL]-5-HYDROXYFURAN-2(5H)-ONE'>LUF</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4dqm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dqm OCA], [https://pdbe.org/4dqm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dqm RCSB], [https://www.ebi.ac.uk/pdbsum/4dqm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dqm ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/RARA_HUMAN RARA_HUMAN] Note=Chromosomal aberrations involving RARA are commonly found in acute promyelocytic leukemia. Translocation t(11;17)(q32;q21) with ZBTB16/PLZF; translocation t(15;17)(q21;q21) with PML; translocation t(5;17)(q32;q11) with NPM. The PML-RARA oncoprotein requires both the PML ring structure and coiled-coil domain for both interaction with UBE2I, nuclear microspeckle location and sumoylation. In addition, the coiled-coil domain functions in blocking RA-mediated transactivation and cell differentiation.
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== Function ==
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[https://www.uniprot.org/uniprot/RARA_HUMAN RARA_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 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. RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis. Has a role in the survival of early spermatocytes at the beginning prophase of meiosis. In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function (By similarity). Regulates expression of target genes in a ligand-dependent manner by recruiting chromatin complexes containing MLL5. Mediates retinoic acid-induced granulopoiesis.<ref>PMID:16417524</ref> <ref>PMID:19850744</ref> <ref>PMID:19377461</ref> <ref>PMID:20215566</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Retinoids display anti-tumour activity on various cancer cells and therefore have been used as important therapeutic agents. However, adverse side effects and RA (retinoic acid) resistance limit further development and clinical application of retinoid-based therapeutic agents. We report in the present paper the identification of a natural marine product that activates RARs (RA receptors) with a chemical structure distinct from retinoids by high-throughput compound library screening. Luffariellolide was uncovered as a novel RAR agonist by inducing co-activator binding to these receptors in vitro, further inhibiting cell growth and regulating RAR target genes in various cancer cells. Structural and molecular studies unravelled a unique binding mode of this natural ligand to RARs with an unexpected covalent modification on the RAR. Functional characterization further revealed that luffariellolide displays chemotherapeutic potentials for overcoming RA resistance in colon cancer cells, suggesting that luffariellolide may represent a unique template for designing novel non-retinoid compounds with advantages over current RA drugs.
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==Function==
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Revealing a natural marine product as a novel agonist for retinoic acid receptors with a unique binding mode and inhibitory effects on cancer cells.,Wang S, Wang Z, Lin S, Zheng W, Wang R, Jin S, Chen J, Jin L, Li Y Biochem J. 2012 Aug 15;446(1):79-87. PMID:22642567<ref>PMID:22642567</ref>
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[[http://www.uniprot.org/uniprot/RARA_HUMAN RARA_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 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. RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis. Has a role in the survival of early spermatocytes at the beginning prophase of meiosis. In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function (By similarity). Regulates expression of target genes in a ligand-dependent manner by recruiting chromatin complexes containing MLL5. Mediates retinoic acid-induced granulopoiesis.<ref>PMID:16417524</ref> <ref>PMID:19850744</ref> <ref>PMID:19377461</ref> <ref>PMID:20215566</ref> [[http://www.uniprot.org/uniprot/NCOA1_HUMAN NCOA1_HUMAN]] Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.<ref>PMID:9427757</ref> <ref>PMID:7481822</ref> <ref>PMID:9223431</ref> <ref>PMID:9296499</ref> <ref>PMID:9223281</ref> <ref>PMID:10449719</ref> <ref>PMID:12954634</ref>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4dqm]] 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=4DQM OCA].
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</div>
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<div class="pdbe-citations 4dqm" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:022642567</ref><references group="xtra"/><references/>
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*[[Retinoic acid receptor 3D structures|Retinoic acid receptor 3D structures]]
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[[Category: Histone acetyltransferase]]
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== References ==
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[[Category: Human]]
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<references/>
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[[Category: Chen, J.]]
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__TOC__
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[[Category: Jin, L.]]
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</StructureSection>
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[[Category: Jin, S.]]
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[[Category: Homo sapiens]]
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[[Category: Li, Y.]]
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[[Category: Large Structures]]
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[[Category: Lin, S.]]
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[[Category: Chen J]]
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[[Category: Wang, R.]]
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[[Category: Jin L]]
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[[Category: Wang, S.]]
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[[Category: Jin S]]
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[[Category: Wang, Z.]]
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[[Category: Li Y]]
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[[Category: Zheng, W.]]
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[[Category: Lin S]]
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[[Category: Ligand binding domain]]
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[[Category: Wang R]]
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[[Category: Nuclear receptor transcription factor]]
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[[Category: Wang S]]
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[[Category: Nucleus]]
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[[Category: Wang Z]]
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[[Category: Transcription regulation]]
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[[Category: Zheng W]]
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[[Category: Transcription-transferase complex]]
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Current revision

Revealing a marine natural product as a novel agonist for retinoic acid receptors with a unique binding mode and antitumor activity

PDB ID 4dqm

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