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New page: left|200px<br /> <applet load="1nrl" size="450" color="white" frame="true" align="right" spinBox="true" caption="1nrl, resolution 2.00Å" /> '''Crystal Structure o...
 
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[[Image:1nrl.gif|left|200px]]<br />
<applet load="1nrl" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1nrl, resolution 2.00&Aring;" />
'''Crystal Structure of the human PXR-LBD in complex with an SRC-1 coactivator peptide and SR12813'''<br />


==Overview==
==Crystal Structure of the human PXR-LBD in complex with an SRC-1 coactivator peptide and SR12813==
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.
<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 [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. 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 [https://proteopedia.org/fgij/fg.htm?mol=1NRL FirstGlance]. <br>
</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&#8491;</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1nrl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1nrl OCA], [https://pdbe.org/1nrl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1nrl RCSB], [https://www.ebi.ac.uk/pdbsum/1nrl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1nrl ProSAT]</span></td></tr>
</table>
== Function ==
[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>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/nr/1nrl_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1nrl ConSurf].
<div style="clear:both"></div>


==Disease==
==See Also==
Known diseases associated with this structure: Adrenoleukodystrophy, neonatal OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600414 600414]], Zellweger syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600414 600414]]
*[[Pregnane X receptor 3D structures|Pregnane X receptor 3D structures]]
 
== References ==
==About this Structure==
<references/>
1NRL is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SRL as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1NRL OCA].
__TOC__
 
</StructureSection>
==Reference==
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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12909012 12909012]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Protein complex]]
[[Category: Large Structures]]
[[Category: Davis-Searles, P.R.]]
[[Category: Davis-Searles PR]]
[[Category: Lambert, M.H.]]
[[Category: Lambert MH]]
[[Category: Redinbo, M.R.]]
[[Category: Redinbo MR]]
[[Category: Watkins, R.E.]]
[[Category: Watkins RE]]
[[Category: SRL]]
[[Category: coactivator]]
[[Category: ligand binding domain]]
[[Category: nuclear receptor]]
[[Category: pxr]]
[[Category: src-1]]
[[Category: xenobiotic]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:24:27 2007''

Latest revision as of 07:59, 14 February 2024

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

1nrl, resolution 2.00Å

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