7Z7D

Tubulin-Todalam-Vinblastine-complex

7Z7D の概要

• エントリーDOI: 10.2210/pdb7z7d/pdb
• 関連するPDBエントリー: 5SB3 5SB4 5SB5 5SB6 5SB7
• 分子名称: Tubulin alpha-1B chain, (2ALPHA,2'BETA,3BETA,4ALPHA,5BETA)-VINCALEUKOBLASTINE, N-(4-{2-[3-(trifluoromethyl)anilino]-1,3-thiazol-4-yl}phenyl)acetamide, ... (13 entities in total)
• 機能のキーワード: cell cycle, tubulin fold, cytoskeleton, microtubule
• 由来する生物種: Rattus norvegicus (Norway rat); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 265734.72

構造登録者

Muehlethaler, T.,Milanos, L.,Ortega, J.A.,Blum, T.B.,Gioia, D.,Roy, B.,Prota, A.E.,Cavalli, A.,Steinmetz, M.O. (登録日: 2022-03-15, 公開日: 2022-04-27, 最終更新日: 2024-01-31)

主引用文献

Muhlethaler, T.,Milanos, L.,Ortega, J.A.,Blum, T.B.,Gioia, D.,Roy, B.,Prota, A.E.,Cavalli, A.,Steinmetz, M.O.
Rational Design of a Novel Tubulin Inhibitor with a Unique Mechanism of Action.
Angew.Chem.Int.Ed.Engl., 61:e202204052-e202204052, 2022

PubMed Abstract: In this study, we capitalized on our previously performed crystallographic fragment screen and developed the antitubulin small molecule Todalam with only two rounds of straightforward chemical synthesis. Todalam binds to a novel tubulin site, disrupts microtubule networks in cells, arrests cells in G2/M, induces cell death, and synergizes with vinblastine. The compound destabilizes microtubules by acting as a molecular plug that sterically inhibits the curved-to-straight conformational switch in the α-tubulin subunit, and by sequestering tubulin dimers into assembly incompetent oligomers. Our results describe for the first time the generation of a fully rationally designed small molecule tubulin inhibitor from a fragment, which displays a unique molecular mechanism of action. They thus demonstrate the usefulness of tubulin-binding fragments as valuable starting points for innovative antitubulin drug and chemical probe discovery campaigns.

PubMed: 35404502
DOI: 10.1002/anie.202204052

実験手法

X-RAY DIFFRACTION (2 Å)