6itm
From Proteopedia
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<StructureSection load='6itm' size='340' side='right'caption='[[6itm]], [[Resolution|resolution]] 2.50Å' scene=''> | <StructureSection load='6itm' size='340' side='right'caption='[[6itm]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[6itm]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ITM OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[6itm]] 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=6ITM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ITM FirstGlance]. <br> |
| - | </td></tr><tr id=' | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5Å</td></tr> |
| - | <tr id=' | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AWL:1-adamantyl-[4-(5-chloranyl-2-methyl-phenyl)piperazin-1-yl]methanone'>AWL</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6itm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6itm OCA], [https://pdbe.org/6itm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6itm RCSB], [https://www.ebi.ac.uk/pdbsum/6itm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6itm ProSAT]</span></td></tr> |
</table> | </table> | ||
| - | == Disease == | ||
| - | [[http://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 == | ||
| - | [ | + | [https://www.uniprot.org/uniprot/NR1H4_HUMAN NR1H4_HUMAN] Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.<ref>PMID:10334992</ref> <ref>PMID:10334993</ref> <ref>PMID:12815072</ref> <ref>PMID:15471871</ref> <ref>PMID:12718892</ref> <ref>PMID:18621523</ref> <ref>PMID:19410460</ref> <ref>PMID:19586769</ref> |
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Farnesoid X receptor (FXR) agonists can reverse dysregulated bile acid metabolism, and thus, they are potential therapeutics to prevent and treat nonalcoholic fatty liver disease. The low success rate of FXR agonists' R&D and the side effects of clinical candidates such as obeticholic acid make it urgent to discover new chemotypes. Unfortunately, structure-based virtual screening (SBVS) that can speed up drug discovery has rarely been reported with success for FXR, which was likely hindered by the failure in addressing protein flexibility. To address this issue, we devised human FXR (hFXR)-specific ensemble learning models based on pose filters from 24 agonist-bound hFXR crystal structures and coupled them to traditional SBVS approaches of the FRED docking plus Chemgauss4 scoring function. It turned out that the hFXR-specific pose filter ensemble (PFE) was able to improve ligand enrichment significantly, which rendered 3RUT-based SBVS with its PFE the ideal approach for FXR agonist discovery. By screening of the Specs chemical library and in vitro FXR transactivation bioassay, we identified a new class of FXR agonists with compound XJ034 as the representative, which would have been missed if the PFE was not coupled. Following that, we performed in-depth biological studies which demonstrated that XJ034 resulted in a downtrend of intracellular triglyceride in vitro, significantly decreased the serum/liver TG in high fat diet-induced C57BL/6J obese mice, and more importantly, showed metabolic stabilities in both plasma and liver microsomes. To provide insight into further structure-based lead optimization, we solved the crystal structure of hFXR complexed with compound XJ034, uncovering a unique hydrogen bond between compound XJ034 and residue Y375. The current work highlights the power of our pose filter-based ensemble learning approach in terms of scaffold hopping and provides a promising lead compound for further development. | ||
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| + | Pose Filter-Based Ensemble Learning Enables Discovery of Orally Active, Nonsteroidal Farnesoid X Receptor Agonists.,Xia J, Wang Z, Huan Y, Xue W, Wang X, Wang Y, Liu Z, Hsieh JH, Zhang L, Wu S, Shen Z, Zhang H, Wang XS J Chem Inf Model. 2020 Mar 23;60(3):1202-1214. doi: 10.1021/acs.jcim.9b01030., Epub 2020 Feb 25. PMID:32050066<ref>PMID:32050066</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6itm" style="background-color:#fffaf0;"></div> | ||
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| + | ==See Also== | ||
| + | *[[Bile acid receptor 3D structures|Bile acid receptor 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Homo sapiens]] |
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Wang | + | [[Category: Wang Z]] |
| - | [[Category: Zhang | + | [[Category: Zhang H]] |
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Current revision
Crystal structure of FXR in complex with agonist XJ034
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