5YLJ

Crystal structure of T2R-TTL-Millepachine complex

5YLJ の概要

• エントリーDOI: 10.2210/pdb5ylj/pdb
• 分子名称: Tubulin alpha-1B chain, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, (E)-1-(5-methoxy-2,2-dimethyl-chromen-8-yl)-3-(4-methoxyphenyl)prop-2-en-1-one, ... (13 entities in total)
• 機能のキーワード: colchicine binding domain, tubulin inhibitor, tublin, millepachine, structural protein
• 由来する生物種: Sus scrofa (Pig); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 265314.79

構造登録者

Yang, J.H.,Chen, L.J. (登録日: 2017-10-17, 公開日: 2018-04-11, 最終更新日: 2024-03-27)

主引用文献

Yang, J.H.,Yan, W.,Yu, Y.M.,Wang, Y.X.,Yang, T.,Xue, L.L.,Yuan, X.,Long, C.F.,Liu, Z.W.,Chen, X.X.,Hu, M.S.,Zheng, L.,Qiu, Q.,Pei, H.Y.,Li, D.,Wang, F.,Bai, P.,Wen, J.L.,Ye, H.Y.,Chen, L.J.
The compound millepachine and its derivatives inhibit tubulin polymerization by irreversibly binding to the colchicine-binding site in beta-tubulin.
J. Biol. Chem., 293:9461-9472, 2018

PubMed Abstract: Inhibitors that bind to the paclitaxel- or vinblastine-binding sites of tubulin have been part of the pharmacopoeia of anticancer therapy for decades. However, tubulin inhibitors that bind to the colchicine-binding site are not used in clinical cancer therapy, because of their low therapeutic index. To address multidrug resistance to many conventional tubulin-binding agents, numerous efforts have attempted to clinically develop inhibitors that bind the colchicine-binding site. Previously, we have found that millepachine (MIL), a natural chalcone-type small molecule extracted from the plant , and its two derivatives (MDs) SKLB028 and SKLB050 have potential antitumor activities both and However, their cellular targets and mechanisms are unclear. Here, biochemical and cellular experiments revealed that the MDs directly and irreversibly bind β-tubulin. X-ray crystallography of the tubulin-MD structures disclosed that the MDs bind at the tubulin intradimer interface and to the same site as colchicine and that their binding mode is similar to that of colchicine. Of note, MDs inhibited tubulin polymerization and caused G/M cell-cycle arrest. Comprehensive analysis further revealed that free MIL exhibits an s- conformation, whereas MIL in the colchicine-binding site in tubulin adopts an s- conformation. Moreover, introducing an α-methyl to MDs to increase the proportion of s- conformations augmented MDs' tubulin inhibition activity. Our study uncovers a new class of chalcone-type tubulin inhibitors that bind the colchicine-binding site in β-tubulin and suggests that the s- conformation of these compounds may make them more active anticancer agents.

PubMed: 29691282
DOI: 10.1074/jbc.RA117.001658

実験手法

X-RAY DIFFRACTION (2.7 Å)