5LOV

DZ-2384 tubulin complex

5LOV の概要

• エントリーDOI: 10.2210/pdb5lov/pdb
• 関連するPDBエントリー: 4I55 5J2T
• 分子名称: Tubulin alpha-1B chain, DZ 2384, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 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
• 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: 265023.20

構造登録者

Prota, A.E.,Steinmetz, M.O.,Shore, G.C.,Brouhard, G.,Roulston, A. (登録日: 2016-08-10, 公開日: 2016-11-30, 最終更新日: 2024-01-10)

主引用文献

Wieczorek, M.,Tcherkezian, J.,Bernier, C.,Prota, A.E.,Chaaban, S.,Rolland, Y.,Godbout, C.,Hancock, M.A.,Arezzo, J.C.,Ocal, O.,Rocha, C.,Olieric, N.,Hall, A.,Ding, H.,Bramoulle, A.,Annis, M.G.,Zogopoulos, G.,Harran, P.G.,Wilkie, T.M.,Brekken, R.A.,Siegel, P.M.,Steinmetz, M.O.,Shore, G.C.,Brouhard, G.J.,Roulston, A.
The synthetic diazonamide DZ-2384 has distinct effects on microtubule curvature and dynamics without neurotoxicity.
Sci Transl Med, 8:365ra159-365ra159, 2016

PubMed Abstract: Microtubule-targeting agents (MTAs) are widely used anticancer agents, but toxicities such as neuropathy limit their clinical use. MTAs bind to and alter the stability of microtubules, causing cell death in mitosis. We describe DZ-2384, a preclinical compound that exhibits potent antitumor activity in models of multiple cancer types. It has an unusually high safety margin and lacks neurotoxicity in rats at effective plasma concentrations. DZ-2384 binds the vinca domain of tubulin in a distinct way, imparting structurally and functionally different effects on microtubule dynamics compared to other vinca-binding compounds. X-ray crystallography and electron microscopy studies demonstrate that DZ-2384 causes straightening of curved protofilaments, an effect proposed to favor polymerization of tubulin. Both DZ-2384 and the vinca alkaloid vinorelbine inhibit microtubule growth rate; however, DZ-2384 increases the rescue frequency and preserves the microtubule network in nonmitotic cells and in primary neurons. This differential modulation of tubulin results in a potent MTA therapeutic with enhanced safety.

PubMed: 27856798
DOI: 10.1126/scitranslmed.aag1093

実験手法

X-RAY DIFFRACTION (2.4 Å)