8fmu
From Proteopedia
(Difference between revisions)
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<table><tr><td colspan='2'>[[8fmu]] 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=8FMU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FMU FirstGlance]. <br> | <table><tr><td colspan='2'>[[8fmu]] 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=8FMU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FMU 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]] 2.03Å</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]] 2.03Å</td></tr> | ||
| - | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Y3T:N-(3- | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Y3T:~{N}-(3-chloranyl-4-fluoranyl-phenyl)-3-[4-(dimethylamino)butanoylamino]-4-methoxy-benzamide'>Y3T</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=8fmu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fmu OCA], [https://pdbe.org/8fmu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fmu RCSB], [https://www.ebi.ac.uk/pdbsum/8fmu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fmu ProSAT]</span></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=8fmu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fmu OCA], [https://pdbe.org/8fmu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fmu RCSB], [https://www.ebi.ac.uk/pdbsum/8fmu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fmu ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/TBXT_HUMAN TBXT_HUMAN] Involved in the transcriptional regulation of genes required for mesoderm formation and differentiation. Binds to a palindromic site (called T site) and activates gene transcription when bound to such a site.[UniProtKB:P20293] | [https://www.uniprot.org/uniprot/TBXT_HUMAN TBXT_HUMAN] Involved in the transcriptional regulation of genes required for mesoderm formation and differentiation. Binds to a palindromic site (called T site) and activates gene transcription when bound to such a site.[UniProtKB:P20293] | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Brachyury is an oncogenic transcription factor whose overexpression drives chordoma growth. The downmodulation of brachyury in chordoma cells has demonstrated therapeutic potential, however, as a transcription factor it is classically deemed "undruggable". Given that direct pharmacological intervention against brachyury has proven difficult, attempts at intervention have instead targeted upstream kinases. Recently, afatinib, an FDA-approved kinase inhibitor, has been shown to modulate brachyury levels in multiple chordoma cell lines. Herein, we use afatinib as a lead to undertake a structure-based drug design approach, aided by mass-spectrometry and X-ray crystallography, to develop DHC-156, a small molecule that more selectively binds brachyury and downmodulates it as potently as afatinib. We eliminated kinase-inhibition from this novel scaffold while demonstrating that DHC-156 induces the post-translational downmodulation of brachyury that results in an irreversible impairment of chordoma tumor cell growth. In doing so, we demonstrate the feasibility of direct brachyury modulation, which may further be developed into more potent tool compounds and therapies. | ||
| + | |||
| + | Development of a Small Molecule Downmodulator for the Transcription Factor Brachyury.,Chase DH, Bebenek AM, Nie P, Jaime-Figueroa S, Butrin A, Castro DA, Hines J, Linhares BM, Crews CM Angew Chem Int Ed Engl. 2024 Apr 2;63(14):e202316496. doi: , 10.1002/anie.202316496. Epub 2024 Feb 28. PMID:38348945<ref>PMID:38348945</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 8fmu" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Revision as of 05:02, 18 September 2024
Crystal structure of human Brachyury G177D variant in complex with SJF-4601
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