View source for 8szv


==Crystal structure of pregnane X receptor ligand binding domain complexed with T0901317 analog SJPYT-318==
<StructureSection load='8szv' size='340' side='right'caption='[[8szv]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8szv]] is a 1 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=8SZV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8SZV 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]] 2.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=X1D:N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-[(4-phenoxyphenyl)methyl]benzenesulfonamide'>X1D</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=8szv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8szv OCA], [https://pdbe.org/8szv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8szv RCSB], [https://www.ebi.ac.uk/pdbsum/8szv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8szv 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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The human nuclear receptor (NR) family of transcription factors contains 48 proteins that bind lipophilic molecules. Approved NR therapies have had immense success treating various diseases, but lack of selectivity has hindered efforts to therapeutically target the majority of NRs due to unpredictable off-target effects. The synthetic ligand T0901317 was originally discovered as a potent agonist of liver X receptors (LXRalpha/beta) but subsequently found to target additional NRs, with activation of pregnane X receptor (PXR) being as potent as that of LXRs. We previously showed that directed rigidity reduces PXR binding by T0901317 derivatives through unfavorable protein remodeling. Here, we use a similar approach to achieve selectivity for PXR over other T0901317-targeted NRs. One molecule, SJPYT-318, accomplishes selectivity by favorably utilizing PXR's flexible binding pocket and surprisingly binding in a new mode distinct from the parental T0901317. Our work provides a structure-guided framework to achieve NR selectivity from promiscuous compounds.

Ligand flexibility and binding pocket malleability cooperate to allow selective PXR activation by analogs of a promiscuous nuclear receptor ligand.,Huber AD, Poudel S, Li Y, Lin W, Wu J, Miller DJ, Chen T Structure. 2023 Sep 5:S0969-2126(23)00297-6. doi: 10.1016/j.str.2023.08.020. PMID:37729916<ref>PMID:37729916</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8szv" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chen T]]
[[Category: Huber AD]]
[[Category: Li Y]]
[[Category: Miller DJ]]
[[Category: Poudel S]]