1nrl

From Proteopedia

(Difference between revisions)

Revision as of 08:56, 2 December 2020

Crystal Structure of the human PXR-LBD in complex with an SRC-1 coactivator peptide and SR12813

Structural highlights

1nrl 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:	1ilg, 1ilh, 1m13
Gene:	NR112 or PXR (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The pregnane X receptor (PXR) detects the presence of a wide variety of endogenous and xenobiotic compounds, and is a master regulator of the expression of genes central to drug metabolism and excretion. We present the 2.0A crystal structure of the human PXR ligand-binding domain (LBD) in complex with the cholesterol-lowering compound SR12813 and a 25 amino acid residue fragment of the human steroid receptor coactivator-1 (SRC-1) containing one LXXLL motif. PXR crystallizes as a homodimer in the asymmetric unit in this structure and possesses a novel alpha2 helix adjacent to its ligand-binding cavity. The SRC-1 peptide forms two distinct helices and binds adjacent to the ligand-dependent transactivation AF-2 helix on the surface of PXR. In contrast with previous PXR structures, in which SR12813 bound in multiple orientations, the small SR12813 agonist in this structure binds in a single, unique orientation within the receptor's ligand-binding pocket and contacts the AF-2 helix. Thermal denaturation studies reveal that the SR12813 ligand and SRC-1 coactivator peptide each stabilize the LBD of PXR, and that together they exert an additive effect on the stability of the receptor. These results indicate that the binding of coactivator to the surface of PXR limits the ability of this promiscuous receptor to "breathe" and helps to trap a single, active conformation of SR12813. They further reveal that specificity is required for PXR activation.

Coactivator binding promotes the specific interaction between ligand and the pregnane X receptor.,Watkins RE, Davis-Searles PR, Lambert MH, Redinbo MR J Mol Biol. 2003 Aug 22;331(4):815-28. PMID:12909012^[7]

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

References

↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ Watkins RE, Davis-Searles PR, Lambert MH, Redinbo MR. Coactivator binding promotes the specific interaction between ligand and the pregnane X receptor. J Mol Biol. 2003 Aug 22;331(4):815-28. PMID:12909012

1 Structural highlights
2 Function
3 Evolutionary Conservation
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/1nrl"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of the human PXR-LBD in complex with an SRC-1 coactivator peptide and SR12813==
-<StructureSection load='1nrl' size='340' side='right' caption='[[1nrl]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+<StructureSection load='1nrl' size='340' side='right'caption='[[1nrl]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1nrl]] 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=1NRL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1NRL FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1nrl]] 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=1NRL OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=1NRL FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SRL:[2-(3,5-DI-TERT-BUTYL-4-HYDROXY-PHENYL)-1-(DIETHOXY-PHOSPHORYL)-VINYL]-PHOSPHONIC+ACID+DIETHLYL+ESTER'>SRL</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SRL:[2-(3,5-DI-TERT-BUTYL-4-HYDROXY-PHENYL)-1-(DIETHOXY-PHOSPHORYL)-VINYL]-PHOSPHONIC+ACID+DIETHLYL+ESTER'>SRL</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ilg|1ilg]], [[1ilh|1ilh]], [[1m13|1m13]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1ilg|1ilg]], [[1ilh|1ilh]], [[1m13|1m13]]</div></td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NR112 or PXR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=1nrl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1nrl OCA], [http://pdbe.org/1nrl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1nrl RCSB], [http://www.ebi.ac.uk/pdbsum/1nrl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1nrl ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=1nrl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1nrl OCA], [http://pdbe.org/1nrl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1nrl RCSB], [http://www.ebi.ac.uk/pdbsum/1nrl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1nrl ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 30: / Line 30: @@
 </div>
 <div class="pdbe-citations 1nrl" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Pregnane X receptor|Pregnane X receptor]]
 == References ==
 <references/>
@@ Line 35: / Line 38: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Davis-Searles, P R]]
 [[Category: Lambert, M H]]

1nrl

From Proteopedia

Revision as of 08:56, 2 December 2020

Crystal Structure of the human PXR-LBD in complex with an SRC-1 coactivator peptide and SR12813

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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