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4dm8

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Revision as of 08:19, 27 March 2019

Crystal structure of RARb LBD in complex with 9cis retinoic acid

Structural highlights

4dm8 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:	1xap, 4dm6, 4dma
Gene:	RARB, HAP, NR1B2 (HUMAN)
Activity:	Histone acetyltransferase, with EC number 2.3.1.48
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[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.

Function

[RARB_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 or presence of hormone ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function.^[1] [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.^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

Publication Abstract from PubMed

Transcription regulation by steroid hormones, vitamin derivatives, and metabolites is mediated by nuclear receptors (NRs), which play an important role in ligand-dependent gene expression and human health. NRs function as homodimers or heterodimers and are involved in a combinatorial, coordinated and sequentially orchestrated exchange between coregulators (corepressors, coactivators). The architecture of DNA-bound functional dimers positions the coregulators proteins. We previously demonstrated that retinoic acid (RAR-RXR) and vitamin D3 receptors (VDR-RXR) heterodimers recruit only one coactivator molecule asymmetrically without steric hindrance for the binding of a second cofactor. We now address the problem of homodimers for which the presence of two identical targets enhances the functional importance of the mode of binding. Using structural and biophysical methods and RAR as a model, we could dissect the molecular mechanism of coactivator recruitment to homodimers. Our study reveals an allosteric mechanism whereby binding of a coactivator promotes formation of nonsymmetrical RAR homodimers with a 21 stoichiometry. Ligand conformation and the cofactor binding site of the unbound receptor are affected through the dimer interface. A similar control mechanism is observed with estrogen receptor (ER) thus validating the negative cooperativity model for an established functional homodimer. Correlation with published data on other NRs confirms the general character of this regulatory pathway.

Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors.,Osz J, Brelivet Y, Peluso-Iltis C, Cura V, Eiler S, Ruff M, Bourguet W, Rochel N, Moras D Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):E588-94. Epub 2012 Feb 21. PMID:22355136^[9]

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

References

↑ Hauksdottir H, Farboud B, Privalsky ML. Retinoic acid receptors beta and gamma do not repress, but instead activate target gene transcription in both the absence and presence of hormone ligand. Mol Endocrinol. 2003 Mar;17(3):373-85. Epub 2002 Dec 23. PMID:12554770 doi:10.1210/me.2002-0340
↑ Kalkhoven E, Valentine JE, Heery DM, Parker MG. Isoforms of steroid receptor co-activator 1 differ in their ability to potentiate transcription by the oestrogen receptor. EMBO J. 1998 Jan 2;17(1):232-43. PMID:9427757 doi:10.1093/emboj/17.1.232
↑ Onate SA, Tsai SY, Tsai MJ, O'Malley BW. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science. 1995 Nov 24;270(5240):1354-7. PMID:7481822
↑ Hayashi Y, Ohmori S, Ito T, Seo H. A splicing variant of Steroid Receptor Coactivator-1 (SRC-1E): the major isoform of SRC-1 to mediate thyroid hormone action. Biochem Biophys Res Commun. 1997 Jul 9;236(1):83-7. PMID:9223431 doi:10.1006/bbrc.1997.6911
↑ Spencer TE, Jenster G, Burcin MM, Allis CD, Zhou J, Mizzen CA, McKenna NJ, Onate SA, Tsai SY, Tsai MJ, O'Malley BW. Steroid receptor coactivator-1 is a histone acetyltransferase. Nature. 1997 Sep 11;389(6647):194-8. PMID:9296499 doi:10.1038/38304
↑ Jenster G, Spencer TE, Burcin MM, Tsai SY, Tsai MJ, O'Malley BW. Steroid receptor induction of gene transcription: a two-step model. Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):7879-84. PMID:9223281
↑ Liu Z, Wong J, Tsai SY, Tsai MJ, O'Malley BW. Steroid receptor coactivator-1 (SRC-1) enhances ligand-dependent and receptor-dependent cell-free transcription of chromatin. Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9485-90. PMID:10449719
↑ Litterst CM, Kliem S, Marilley D, Pfitzner E. NCoA-1/SRC-1 is an essential coactivator of STAT5 that binds to the FDL motif in the alpha-helical region of the STAT5 transactivation domain. J Biol Chem. 2003 Nov 14;278(46):45340-51. Epub 2003 Sep 3. PMID:12954634 doi:http://dx.doi.org/10.1074/jbc.M303644200
↑ Osz J, Brelivet Y, Peluso-Iltis C, Cura V, Eiler S, Ruff M, Bourguet W, Rochel N, Moras D. Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors. Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):E588-94. Epub 2012 Feb 21. PMID:22355136 doi:10.1073/pnas.1118192109

1 Structural highlights
2 Disease
3 Function
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/4dm8"

@@ Line 1: / Line 1: @@
 ==Crystal structure of RARb LBD in complex with 9cis retinoic acid==
-<StructureSection load='4dm8' size='340' side='right' caption='[[4dm8]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+<StructureSection load='4dm8' size='340' side='right'caption='[[4dm8]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4dm8]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DM8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DM8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4dm8]] 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=4DM8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DM8 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=REA:RETINOIC+ACID'>REA</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1xap|1xap]], [[4dm6|4dm6]], [[4dma|4dma]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RARB, HAP, NR1B2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4dm8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dm8 OCA], [http://pdbe.org/4dm8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4dm8 RCSB], [http://www.ebi.ac.uk/pdbsum/4dm8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4dm8 ProSAT]</span></td></tr>
@@ Line 30: / Line 31: @@
 </StructureSection>
 [[Category: Histone acetyltransferase]]
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Bourguet, W]]
 [[Category: Cura, V]]

4dm8

From Proteopedia

Revision as of 08:19, 27 March 2019

Crystal structure of RARb LBD in complex with 9cis retinoic acid

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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