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4s14

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Revision as of 01:15, 19 January 2017

Crystal structure of the orphan nuclear receptor RORgamma ligand-binding domain in complex with 4alpha-caboxyl, 4beta-methyl-zymosterol (4ACD8)

Structural highlights

4s14 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	4s15
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[RORG_HUMAN] Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock. [NRIP1_HUMAN] Modulates transcriptional activation by steroid receptors such as NR3C1, NR3C2 and ESR1. Also modulates transcriptional repression by nuclear hormone receptors.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Mice deficient in the nuclear hormone receptor RORgammat have defective development of thymocytes, lymphoid organs, Th17 cells, and type 3 innate lymphoid cells. RORgammat binds to oxysterols derived from cholesterol catabolism, but it is not clear whether these are its natural ligands. Here, we show that sterol lipids are necessary and sufficient to drive RORgammat-dependent transcription. We combined overexpression, RNAi, and genetic deletion of metabolic enzymes to study RORgamma-dependent transcription. Our results are consistent with the RORgammat ligand(s) being a cholesterol biosynthetic intermediate (CBI) downstream of lanosterol and upstream of zymosterol. Analysis of lipids bound to RORgamma identified molecules with molecular weights consistent with CBIs. Furthermore, CBIs stabilized the RORgamma ligand-binding domain and induced coactivator recruitment. Genetic deletion of metabolic enzymes upstream of the RORgammat-ligand(s) affected the development of lymph nodes and Th17 cells. Our data suggest that CBIs play a role in lymphocyte development potentially through regulation of RORgammat.

Identification of Natural RORgamma Ligands that Regulate the Development of Lymphoid Cells.,Santori FR, Huang P, van de Pavert SA, Douglass EF Jr, Leaver DJ, Haubrich BA, Keber R, Lorbek G, Konijn T, Rosales BN, Rozman D, Horvat S, Rahier A, Mebius RE, Rastinejad F, Nes WD, Littman DR Cell Metab. 2015 Feb 3;21(2):286-97. doi: 10.1016/j.cmet.2015.01.004. PMID:25651181^[7]

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

References

↑ Cavailles V, Dauvois S, L'Horset F, Lopez G, Hoare S, Kushner PJ, Parker MG. Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO J. 1995 Aug 1;14(15):3741-51. PMID:7641693
↑ Subramaniam N, Treuter E, Okret S. Receptor interacting protein RIP140 inhibits both positive and negative gene regulation by glucocorticoids. J Biol Chem. 1999 Jun 18;274(25):18121-7. PMID:10364267
↑ Vo N, Fjeld C, Goodman RH. Acetylation of nuclear hormone receptor-interacting protein RIP140 regulates binding of the transcriptional corepressor CtBP. Mol Cell Biol. 2001 Sep;21(18):6181-8. PMID:11509661
↑ Zennaro MC, Souque A, Viengchareun S, Poisson E, Lombes M. A new human MR splice variant is a ligand-independent transactivator modulating corticosteroid action. Mol Endocrinol. 2001 Sep;15(9):1586-98. PMID:11518808
↑ Teyssier C, Belguise K, Galtier F, Cavailles V, Chalbos D. Receptor-interacting protein 140 binds c-Jun and inhibits estradiol-induced activator protein-1 activity by reversing glucocorticoid receptor-interacting protein 1 effect. Mol Endocrinol. 2003 Feb;17(2):287-99. PMID:12554755 doi:http://dx.doi.org/10.1210/me.2002-0324
↑ Castet A, Boulahtouf A, Versini G, Bonnet S, Augereau P, Vignon F, Khochbin S, Jalaguier S, Cavailles V. Multiple domains of the Receptor-Interacting Protein 140 contribute to transcription inhibition. Nucleic Acids Res. 2004 Apr 1;32(6):1957-66. Print 2004. PMID:15060175 doi:http://dx.doi.org/10.1093/nar/gkh524
↑ Santori FR, Huang P, van de Pavert SA, Douglass EF Jr, Leaver DJ, Haubrich BA, Keber R, Lorbek G, Konijn T, Rosales BN, Rozman D, Horvat S, Rahier A, Mebius RE, Rastinejad F, Nes WD, Littman DR. Identification of Natural RORgamma Ligands that Regulate the Development of Lymphoid Cells. Cell Metab. 2015 Feb 3;21(2):286-97. doi: 10.1016/j.cmet.2015.01.004. PMID:25651181 doi:http://dx.doi.org/10.1016/j.cmet.2015.01.004

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4s14"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the orphan nuclear receptor RORgamma ligand-binding domain in complex with 4alpha-caboxyl, 4beta-methyl-zymosterol (4ACD8)==
 <StructureSection load='4s14' size='340' side='right' caption='[[4s14]], [[Resolution|resolution]] 3.54&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4D8:(3BETA,4ALPHA,5BETA,14BETA)-3-HYDROXY-4-METHYLCHOLESTA-8,24-DIENE-4-CARBOXYLIC+ACID'>4D8</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4s15|4s15]]</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=4s14 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4s14 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4s14 RCSB], [http://www.ebi.ac.uk/pdbsum/4s14 PDBsum]</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=4s14 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4s14 OCA], [http://pdbe.org/4s14 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4s14 RCSB], [http://www.ebi.ac.uk/pdbsum/4s14 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4s14 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4s14" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4s14

From Proteopedia

Revision as of 01:15, 19 January 2017

Crystal structure of the orphan nuclear receptor RORgamma ligand-binding domain in complex with 4alpha-caboxyl, 4beta-methyl-zymosterol (4ACD8)

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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