8CDN

Crystal structure of human Brachyury in complex with a single T box binding element DNA

8CDN の概要

• エントリーDOI: 10.2210/pdb8cdn/pdb
• 分子名称: T-box transcription factor T, DNA (5'-D(*AP*GP*GP*TP*GP*TP*GP*AP*GP*CP*CP*T)-3'), DNA (5'-D(*AP*GP*GP*CP*TP*CP*AP*CP*AP*CP*CP*T)-3'), ... (4 entities in total)
• 機能のキーワード: brachyury, tbxt, transcription
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 29348.15

構造登録者

Newman, J.A.,Gavard, A.E.,von Delft, F.,Gileadi, O.,Bountra, C. (登録日: 2023-01-31, 公開日: 2023-03-22, 最終更新日: 2025-02-26)

主引用文献

Newman, J.A.,Gavard, A.E.,Imprachim, N.,Aitkenhead, H.,Sheppard, H.E.,Te Poele, R.,Clarke, P.A.,Hossain, M.A.,Temme, L.,Oh, H.J.,Wells, C.I.,Davis-Gilbert, Z.W.,Workman, P.,Gileadi, O.,Drewry, D.H.
Structural insights into human brachyury DNA recognition and discovery of progressible binders for cancer therapy.
Nat Commun, 16:1596-1596, 2025

PubMed Abstract: 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 µM 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.

PubMed: 39952925
DOI: 10.1038/s41467-025-56213-1

実験手法

X-RAY DIFFRACTION (2.55 Å)