6tfi

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==PXR IN COMPLEX WITH THROMBIN INHIBITOR COMPOUND 17==
==PXR IN COMPLEX WITH THROMBIN INHIBITOR COMPOUND 17==
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<StructureSection load='6tfi' size='340' side='right'caption='[[6tfi]]' scene=''>
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<StructureSection load='6tfi' size='340' side='right'caption='[[6tfi]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TFI OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TFI FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6tfi]] is a 2 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=6TFI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TFI FirstGlance]. <br>
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</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=6tfi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tfi OCA], [http://pdbe.org/6tfi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tfi RCSB], [http://www.ebi.ac.uk/pdbsum/6tfi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tfi ProSAT]</span></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.85&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=N6H:[2-[(3-chlorophenyl)methylamino]-7-methoxy-1,3-benzoxazol-5-yl]-(2,2-dimethylmorpholin-4-yl)methanone'>N6H</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6tfi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tfi OCA], [https://pdbe.org/6tfi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tfi RCSB], [https://www.ebi.ac.uk/pdbsum/6tfi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tfi ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
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[https://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.
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== Function ==
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[https://www.uniprot.org/uniprot/NCOA1_HUMAN NCOA1_HUMAN] Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.<ref>PMID:9427757</ref> <ref>PMID:7481822</ref> <ref>PMID:9223431</ref> <ref>PMID:9296499</ref> <ref>PMID:9223281</ref> <ref>PMID:10449719</ref> <ref>PMID:12954634</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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Despite extensive research on small molecule thrombin inhibitors for oral application in the past decades, only a single double prodrug with very modest oral bioavailability has reached human therapy as a marketed drug. We have undertaken major efforts to identify neutral, non-prodrug inhibitors. Using a holistic analysis of all available internal data, we were able to build computational models and apply these for the selection of a lead series with the highest possibility of achieving oral bioavailability. In our design, we relied on protein structure knowledge to address potency and identified a small window of favorable physicochemical properties to balance absorption and metabolic stability. Protein structure information on the pregnane X receptor helped in overcoming a persistent cytochrome P450 3A4 induction problem. The selected compound series was optimized to a highly potent, neutral, non-prodrug thrombin inhibitor by designing, synthesizing, and testing derivatives. The resulting optimized compound, BAY1217224, has reached first clinical trials, which have confirmed the desired pharmacokinetic properties.
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Design, Synthesis, and Pharmacological Characterization of a Neutral, Non-Prodrug Thrombin Inhibitor with Good Oral Pharmacokinetics.,Hillisch A, Gericke KM, Allerheiligen S, Roehrig S, Schaefer M, Tersteegen A, Schulz S, Lienau P, Gnoth M, Puetter V, Hillig RC, Heitmeier S J Med Chem. 2020 Oct 27. doi: 10.1021/acs.jmedchem.0c01035. PMID:33108181<ref>PMID:33108181</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6tfi" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Pregnane X receptor 3D structures|Pregnane X receptor 3D structures]]
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Hillig RC]]
[[Category: Hillig RC]]
[[Category: Puetter V]]
[[Category: Puetter V]]

Current revision

PXR IN COMPLEX WITH THROMBIN INHIBITOR COMPOUND 17

PDB ID 6tfi

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