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==STRUCTURE OF HUMAN PREGNANE X RECEPTOR LIGAND BINDING DOMAIN BOUND TETHERED WITH SRC co-activator peptide and Compound 25a AKA BICYCLIC HEXAFLUOROISOPROPYL 2 ALCOHOL SULFONAMIDES==
==STRUCTURE OF HUMAN PREGNANE X RECEPTOR LIGAND BINDING DOMAIN BOUND TETHERED WITH SRC co-activator peptide and Compound 25a AKA BICYCLIC HEXAFLUOROISOPROPYL 2 ALCOHOL SULFONAMIDES==
<StructureSection load='6bns' size='340' side='right' caption='[[6bns]], [[Resolution|resolution]] 2.56&Aring;' scene=''>
<StructureSection load='6bns' size='340' side='right'caption='[[6bns]], [[Resolution|resolution]] 2.56&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6bns]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BNS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BNS FirstGlance]. <br>
<table><tr><td colspan='2'>[[6bns]] 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=6BNS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BNS FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=XGH:2-[(2S)-4-[(4-fluorophenyl)sulfonyl]-7-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-3,4-dihydro-2H-1,4-benzothiazin-2-yl]-N-(2-hydroxy-2-methylpropyl)acetamide'>XGH</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]] 2.56&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=XGH:2-[(2S)-4-[(4-fluorophenyl)sulfonyl]-7-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-3,4-dihydro-2H-1,4-benzothiazin-2-yl]-N-(2-hydroxy-2-methylpropyl)acetamide'>XGH</scene></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=6bns FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bns OCA], [http://pdbe.org/6bns PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bns RCSB], [http://www.ebi.ac.uk/pdbsum/6bns PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bns ProSAT]</span></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=6bns FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bns OCA], [https://pdbe.org/6bns PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6bns RCSB], [https://www.ebi.ac.uk/pdbsum/6bns PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6bns ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[https://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.
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/NR1I2_HUMAN NR1I2_HUMAN]] Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.<ref>PMID:9727070</ref> <ref>PMID:11668216</ref> <ref>PMID:11297522</ref> <ref>PMID:19297428</ref> <ref>PMID:12578355</ref> <ref>PMID:18768384</ref>
[https://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> [https://www.uniprot.org/uniprot/NR1I2_HUMAN NR1I2_HUMAN] Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.<ref>PMID:9727070</ref> <ref>PMID:11668216</ref> <ref>PMID:11297522</ref> <ref>PMID:19297428</ref> <ref>PMID:12578355</ref> <ref>PMID:18768384</ref>  
 
==See Also==
*[[Pregnane X receptor 3D structures|Pregnane X receptor 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Histone acetyltransferase]]
[[Category: Homo sapiens]]
[[Category: ARIENZO, C D]]
[[Category: Large Structures]]
[[Category: BARRISH, J C]]
[[Category: ARIENZO CD]]
[[Category: BOROWSKI, V]]
[[Category: BARRISH JC]]
[[Category: CAMAC, D M]]
[[Category: BOROWSKI V]]
[[Category: CARTER, P H]]
[[Category: CAMAC DM]]
[[Category: DABROS, M]]
[[Category: CARTER PH]]
[[Category: DHAR, T G]]
[[Category: DABROS M]]
[[Category: DUAN, J J.W]]
[[Category: DHAR TG]]
[[Category: FOSTER, W]]
[[Category: DUAN JJW]]
[[Category: GALELLA, M A]]
[[Category: FOSTER W]]
[[Category: GONG, H]]
[[Category: GALELLA MA]]
[[Category: GUPTA, A K]]
[[Category: GONG H]]
[[Category: HAQUE, L]]
[[Category: GUPTA AK]]
[[Category: HEMAGIRI, H]]
[[Category: HAQUE L]]
[[Category: KARMAKAR, A]]
[[Category: HEMAGIRI H]]
[[Category: KHAN, J A]]
[[Category: KARMAKAR A]]
[[Category: LU, Z]]
[[Category: KHAN JA]]
[[Category: PUDZIANOWSKI, A A]]
[[Category: LU Z]]
[[Category: RAUT, D K]]
[[Category: PUDZIANOWSKI AA]]
[[Category: SACK, J S]]
[[Category: RAUT DK]]
[[Category: SALTER-CID, L M]]
[[Category: SACK JS]]
[[Category: SHEN, D R]]
[[Category: SALTER-CID LM]]
[[Category: SOMERVILLE, J E]]
[[Category: SHEN DR]]
[[Category: STACHURA, S]]
[[Category: SOMERVILLE JE]]
[[Category: SUN, H]]
[[Category: STACHURA S]]
[[Category: WANG, F]]
[[Category: SUN H]]
[[Category: WEIGELT, C A]]
[[Category: WANG F]]
[[Category: WEINSTEIN, D S]]
[[Category: WEIGELT CA]]
[[Category: WU, D R]]
[[Category: WEINSTEIN DS]]
[[Category: XIE, J H]]
[[Category: WU DR]]
[[Category: YARDE, M]]
[[Category: XIE JH]]
[[Category: ZHAO, Q]]
[[Category: YARDE M]]
[[Category: Ligand]]
[[Category: ZHAO Q]]
[[Category: Multiple binding mode]]
[[Category: Nuclear hormone receptor]]
[[Category: Nuclear protein]]
[[Category: Nuclear receptor]]
[[Category: Promiscuous]]
[[Category: Xenobiotic]]

Latest revision as of 17:22, 13 March 2024

STRUCTURE OF HUMAN PREGNANE X RECEPTOR LIGAND BINDING DOMAIN BOUND TETHERED WITH SRC co-activator peptide and Compound 25a AKA BICYCLIC HEXAFLUOROISOPROPYL 2 ALCOHOL SULFONAMIDESSTRUCTURE OF HUMAN PREGNANE X RECEPTOR LIGAND BINDING DOMAIN BOUND TETHERED WITH SRC co-activator peptide and Compound 25a AKA BICYCLIC HEXAFLUOROISOPROPYL 2 ALCOHOL SULFONAMIDES

Structural highlights

6bns 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 2.56Å
Ligands:
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

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.[1] [2] [3] [4] [5] [6] [7] NR1I2_HUMAN Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.[8] [9] [10] [11] [12] [13]

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest. 1998 Sep 1;102(5):1016-23. PMID:9727070 doi:10.1172/JCI3703
  9. ↑ Zhang J, Kuehl P, Green ED, Touchman JW, Watkins PB, Daly A, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Wrighton SA, Hancock M, Kim RB, Strom S, Thummel K, Russell CG, Hudson JR Jr, Schuetz EG, Boguski MS. The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants. Pharmacogenetics. 2001 Oct;11(7):555-72. PMID:11668216
  10. ↑ Geick A, Eichelbaum M, Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem. 2001 May 4;276(18):14581-7. Epub 2001 Jan 31. PMID:11297522 doi:10.1074/jbc.M010173200
  11. ↑ Li Y, Ross-Viola JS, Shay NF, Moore DD, Ricketts ML. Human CYP3A4 and murine Cyp3A11 are regulated by equol and genistein via the pregnane X receptor in a species-specific manner. J Nutr. 2009 May;139(5):898-904. doi: 10.3945/jn.108.103572. Epub 2009 Mar 18. PMID:19297428 doi:10.3945/jn.108.103572
  12. ↑ Watkins RE, Maglich JM, Moore LB, Wisely GB, Noble SM, Davis-Searles PR, Lambert MH, Kliewer SA, Redinbo MR. 2.1 A crystal structure of human PXR in complex with the St. John's wort compound hyperforin. Biochemistry. 2003 Feb 18;42(6):1430-8. PMID:12578355 doi:10.1021/bi0268753
  13. ↑ Teotico DG, Bischof JJ, Peng L, Kliewer SA, Redinbo MR. Structural basis of human pregnane X receptor activation by the hops constituent colupulone. Mol Pharmacol. 2008 Dec;74(6):1512-20. doi: 10.1124/mol.108.050732. Epub 2008 Sep, 2. PMID:18768384 doi:10.1124/mol.108.050732

6bns, resolution 2.56Å

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