5JVD

Tubulin-TUB092 complex

5JVD の概要

• エントリーDOI: 10.2210/pdb5jvd/pdb
• 分子名称: Tubulin alpha-1B chain, GUANOSINE-5'-DIPHOSPHATE, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (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 (Rat); 詳細
• 細胞内の位置: Cytoplasm, cytoskeleton: P81947 Q6B856; Golgi apparatus : P63043
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 265507.33

構造登録者

Canela, M.-D.,Noppen, S.,Bueno, O.,Prota, A.E.,Bargsten, K.,Saez-Calvo, G.,Jimeno, M.-L.,Benkheil, M.,Ribatti, D.,Velazquez, S.,Camarasa, M.-J.,Diaz, J.F.,Steinmetz, M.O.,Priego, E.-M.,Perez-Perez, M.-J.,Liekens, S. (登録日: 2016-05-11, 公開日: 2016-06-08, 最終更新日: 2024-05-08)

主引用文献

Canela, M.D.,Noppen, S.,Bueno, O.,Prota, A.E.,Bargsten, K.,Saez-Calvo, G.,Jimeno, M.L.,Benkheil, M.,Ribatti, D.,Velazquez, S.,Camarasa, M.J.,Diaz, J.F.,Steinmetz, M.O.,Priego, E.M.,Perez-Perez, M.J.,Liekens, S.
Antivascular and antitumor properties of the tubulin-binding chalcone TUB091.
Oncotarget, 8:14325-14342, 2017

PubMed Abstract: We investigated the microtubule-destabilizing, vascular-targeting, anti-tumor and anti-metastatic activities of a new series of chalcones, whose prototype compound is (E)-3-(3''-amino-4''-methoxyphenyl)-1-(5'-methoxy-3',4'-methylendioxyphenyl)-2-methylprop-2-en-1-one (TUB091). X-ray crystallography showed that these chalcones bind to the colchicine site of tubulin and therefore prevent the curved-to-straight structural transition of tubulin, which is required for microtubule formation. Accordingly, TUB091 inhibited cancer and endothelial cell growth, induced G2/M phase arrest and apoptosis at 1-10 nM. In addition, TUB091 displayed vascular disrupting effects in vitro and in the chicken chorioallantoic membrane (CAM) assay at low nanomolar concentrations. A water-soluble L-Lys-L-Pro derivative of TUB091 (i.e. TUB099) showed potent antitumor activity in melanoma and breast cancer xenograft models by causing rapid intratumoral vascular shutdown and massive tumor necrosis. TUB099 also displayed anti-metastatic activity similar to that of combretastatin A4-phosphate. Our data indicate that this novel class of chalcones represents interesting lead molecules for the design of vascular disrupting agents (VDAs). Moreover, we provide evidence that our prodrug approach may be valuable for the development of anti-cancer drugs.

PubMed: 27224920
DOI: 10.18632/oncotarget.9527

実験手法

X-RAY DIFFRACTION (2.393 Å)