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==STRUCTURE OF HUMAN PREGNANE X RECEPTOR LIGAND BINDING DOMAIN BOUND WITH ADNECTIN-1 AND COMPOUND-1==
==STRUCTURE OF HUMAN PREGNANE X RECEPTOR LIGAND BINDING DOMAIN BOUND WITH ADNECTIN-1 AND COMPOUND-1==
<StructureSection load='4s0t' size='340' side='right' caption='[[4s0t]], [[Resolution|resolution]] 3.14&Aring;' scene=''>
<StructureSection load='4s0t' size='340' side='right'caption='[[4s0t]], [[Resolution|resolution]] 3.14&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4s0t]] 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=4S0T OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4S0T FirstGlance]. <br>
<table><tr><td colspan='2'>[[4s0t]] 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=4S0T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4S0T FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=40U:N-{(2R)-1-[(4S)-4-(4-CHLOROPHENYL)-4-HYDROXY-3,3-DIMETHYLPIPERIDIN-1-YL]-3-METHYL-1-OXOBUTAN-2-YL}-2-CYCLOPROPYLACETAMIDE'>40U</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]] 3.14&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4xhd|4xhd]], [[4s0s|4s0s]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=40U:N-{(2R)-1-[(4S)-4-(4-CHLOROPHENYL)-4-HYDROXY-3,3-DIMETHYLPIPERIDIN-1-YL]-3-METHYL-1-OXOBUTAN-2-YL}-2-CYCLOPROPYLACETAMIDE'>40U</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NR1I2, 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'>[https://proteopedia.org/fgij/fg.htm?mol=4s0t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4s0t OCA], [https://pdbe.org/4s0t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4s0t RCSB], [https://www.ebi.ac.uk/pdbsum/4s0t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4s0t ProSAT]</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=4s0t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4s0t OCA], [http://pdbe.org/4s0t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4s0t RCSB], [http://www.ebi.ac.uk/pdbsum/4s0t PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4s0t ProSAT]</span></td></tr>
</table>
</table>
== 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/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>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The human pregnane X receptor (PXR) is a promiscuous nuclear receptor that functions as a sensor to a wide variety of xenobiotics and regulates expression of several drug metabolizing enzymes and transporters. We have generated "Adnectins", derived from 10th fibronectin type III domain (10Fn3), that target the PXR ligand binding domain (LBD) interactions with the steroid receptor co-activator-1 (SRC-1) peptide, displacing SRC-1 binding. Adnectins are structurally homologous to the immunoglobulin superfamily. Three different co-crystal structures of PXR LBD with Adnectin-1 and CCR1 (CC chemokine receptor-1) antagonist Compound-1 were determined. This structural information was used to modulate PXR affinity for a related CCR1 antagonist compound that entered into clinical trials for rheumatoid arthritis. The structures of PXR with Adnectin-1 reveal specificity of Adnectin-1 in not only targeting the interface of the SRC-1 interactions but also engaging the same set of residues that are involved in binding of SRC-1 to PXR. Substituting SRC-1 with Adnectin-1 does not alter the binding conformation of Compound-1 in the ligand binding pocket. The structure also reveals the possibility of using Adnectins as crystallization chaperones to generate structures of PXR with compounds of interest.


Developing Adnectins That Target SRC Co-Activator Binding to PXR: A Structural Approach toward Understanding Promiscuity of PXR.,Khan JA, Camac DM, Low S, Tebben AJ, Wensel DL, Wright MC, Su J, Jenny V, Gupta RD, Ruzanov M, Russo KA, Bell A, An Y, Bryson JW, Gao M, Gambhire P, Baldwin ET, Gardner D, Cavallaro CL, Duncia JV, Hynes J Jr J Mol Biol. 2015 Jan 8. pii: S0022-2836(15)00002-9. doi:, 10.1016/j.jmb.2014.12.022. PMID:25579995<ref>PMID:25579995</ref>
==See Also==
 
*[[Pregnane X receptor 3D structures|Pregnane X receptor 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4s0t" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Camac, D M]]
[[Category: Large Structures]]
[[Category: Khan, J A]]
[[Category: Camac DM]]
[[Category: Multiple binding mode]]
[[Category: Khan JA]]
[[Category: Nuclear hormone receptor]]
[[Category: Nuclear receptor]]
[[Category: Promiscuous]]
[[Category: Transcription]]
[[Category: Xenobiotic]]

Latest revision as of 12:57, 1 March 2024

STRUCTURE OF HUMAN PREGNANE X RECEPTOR LIGAND BINDING DOMAIN BOUND WITH ADNECTIN-1 AND COMPOUND-1

4s0t, resolution 3.14Å

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