6f58: Difference between revisions
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==Crystal structure of human Brachyury (T) in complex with DNA== | ==Crystal structure of human Brachyury (T) in complex with DNA== | ||
<StructureSection load='6f58' size='340' side='right' caption='[[6f58]], [[Resolution|resolution]] 2.25Å' scene=''> | <StructureSection load='6f58' size='340' side='right'caption='[[6f58]], [[Resolution|resolution]] 2.25Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6f58]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6F58 OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6f58]] 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=6F58 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6F58 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</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]] 2.253Å</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</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=6f58 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f58 OCA], [https://pdbe.org/6f58 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6f58 RCSB], [https://www.ebi.ac.uk/pdbsum/6f58 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6f58 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | == Disease == | ||
[ | [https://www.uniprot.org/uniprot/TBXT_HUMAN TBXT_HUMAN] Thoracolumbosacral spina bifida cystica;Cervicothoracic spina bifida cystica;Lumbosacral spina bifida cystica;Cervicothoracic spina bifida aperta;Upper thoracic spina bifida aperta;Lumbosacral spina bifida aperta;Thoracolumbosacral spina bifida aperta;Cervical spina bifida cystica;Upper thoracic spina bifida cystica;Total spina bifida aperta;Chordoma;Total spina bifida cystica;Cervical spina bifida aperta;Sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome. Disease susceptibility is associated with variations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. Susceptibility to development of chordomas is due to a T gene duplication. The disease is caused by mutations affecting the gene represented in this entry. | ||
== 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] | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Brachyury is a transcription factor that plays an essential role in tumour growth of the rare bone cancer chordoma and is implicated in other solid tumours. Brachyury is minimally expressed in healthy tissues, making it a potential therapeutic target. Unfortunately, as a ligandless transcription factor, brachyury has historically been considered undruggable. To investigate direct targeting of brachyury by small molecules, we determine the structure of human brachyury both alone and in complex with DNA. The structures provide insights into DNA binding and the context of the chordoma associated G177D variant. We use crystallographic fragment screening to identify hotspots on numerous pockets on the brachyury surface. Finally, we perform follow-up chemistry on fragment hits and describe the progression of a thiazole chemical series into binders with low microM potency. Thus we show that brachyury is ligandable and provide an example of how crystallographic fragment screening may be used to target protein classes that are difficult to address using other approaches. | |||
Structural insights into human brachyury DNA recognition and discovery of progressible binders for cancer therapy.,Newman JA, Gavard AE, Imprachim N, Aitkenhead H, Sheppard HE, Te Poele R, Clarke PA, Hossain MA, Temme L, Oh HJ, Wells CI, Davis-Gilbert ZW, Workman P, Gileadi O, Drewry DH Nat Commun. 2025 Feb 14;16(1):1596. doi: 10.1038/s41467-025-56213-1. PMID:39952925<ref>PMID:39952925</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6f58" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Brachyury|Brachyury]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Arrowsmith CH]] | ||
[[Category: | [[Category: Bountra C]] | ||
[[Category: Edwards | [[Category: Burgess-Brown NA]] | ||
[[Category: Gavard | [[Category: Edwards A]] | ||
[[Category: Gileadi | [[Category: Gavard AE]] | ||
[[Category: Krojer | [[Category: Gileadi O]] | ||
[[Category: Newman | [[Category: Krojer T]] | ||
[[Category: Shrestha | [[Category: Newman JA]] | ||
[[Category: | [[Category: Shrestha L]] | ||
[[Category: Von Delft F]] | |||
Latest revision as of 22:26, 26 February 2025
Crystal structure of human Brachyury (T) in complex with DNACrystal structure of human Brachyury (T) in complex with DNA
Structural highlights
DiseaseTBXT_HUMAN Thoracolumbosacral spina bifida cystica;Cervicothoracic spina bifida cystica;Lumbosacral spina bifida cystica;Cervicothoracic spina bifida aperta;Upper thoracic spina bifida aperta;Lumbosacral spina bifida aperta;Thoracolumbosacral spina bifida aperta;Cervical spina bifida cystica;Upper thoracic spina bifida cystica;Total spina bifida aperta;Chordoma;Total spina bifida cystica;Cervical spina bifida aperta;Sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome. Disease susceptibility is associated with variations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. Susceptibility to development of chordomas is due to a T gene duplication. The disease is caused by mutations affecting the gene represented in this entry. FunctionTBXT_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] Publication Abstract from PubMedBrachyury is a transcription factor that plays an essential role in tumour growth of the rare bone cancer chordoma and is implicated in other solid tumours. Brachyury is minimally expressed in healthy tissues, making it a potential therapeutic target. Unfortunately, as a ligandless transcription factor, brachyury has historically been considered undruggable. To investigate direct targeting of brachyury by small molecules, we determine the structure of human brachyury both alone and in complex with DNA. The structures provide insights into DNA binding and the context of the chordoma associated G177D variant. We use crystallographic fragment screening to identify hotspots on numerous pockets on the brachyury surface. Finally, we perform follow-up chemistry on fragment hits and describe the progression of a thiazole chemical series into binders with low microM potency. Thus we show that brachyury is ligandable and provide an example of how crystallographic fragment screening may be used to target protein classes that are difficult to address using other approaches. Structural insights into human brachyury DNA recognition and discovery of progressible binders for cancer therapy.,Newman JA, Gavard AE, Imprachim N, Aitkenhead H, Sheppard HE, Te Poele R, Clarke PA, Hossain MA, Temme L, Oh HJ, Wells CI, Davis-Gilbert ZW, Workman P, Gileadi O, Drewry DH Nat Commun. 2025 Feb 14;16(1):1596. doi: 10.1038/s41467-025-56213-1. PMID:39952925[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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