5LA6

Tubulin-pironetin complex

5LA6 の概要

• エントリーDOI: 10.2210/pdb5la6/pdb
• 分子名称: Tubulin alpha-1B chain, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, Tubulin beta-2B chain, ... (11 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: 264628.99

構造登録者

Prota, A.E.,Setter, J.,Waight, A.B.,Bargsten, K.,Murga, J.,Diaz, J.F.,Steinmetz, M.O. (登録日: 2016-06-13, 公開日: 2016-07-20, 最終更新日: 2024-11-13)

主引用文献

Prota, A.E.,Setter, J.,Waight, A.B.,Bargsten, K.,Murga, J.,Diaz, J.F.,Steinmetz, M.O.
Pironetin Binds Covalently to alpha Cys316 and Perturbs a Major Loop and Helix of alpha-Tubulin to Inhibit Microtubule Formation.
J.Mol.Biol., 428:2981-2988, 2016

PubMed Abstract: Microtubule-targeting agents are among the most powerful drugs used in chemotherapy to treat cancer patients. Pironetin is a natural product that displays promising anticancer properties by binding to and potently inhibiting tubulin assembly into microtubules; however, its molecular mechanism of action remained obscure. Here, we solved the crystal structure of the tubulin-pironetin complex and found that the compound covalently binds to Cys316 of α-tubulin. The structure further revealed that pironetin perturbs the T7 loop and helix H8 of α-tubulin. Since both these elements are essential for establishing longitudinal tubulin contacts in microtubules, this result explains how pironetin inhibits the formation of microtubules. Together, our data define the molecular details of the pironetin binding site on α-tubulin and thus offer a promising basis for the rational design of pironetin variants with improved activity profiles. They further extend our knowledge on strategies evolved by natural products to target and perturb the microtubule cytoskeleton.

PubMed: 27395016
DOI: 10.1016/j.jmb.2016.06.023

実験手法

X-RAY DIFFRACTION (2.1 Å)