Pironetin reacts covalently with cysteine-316 of α-tubulin to destabilize microtubule

Jianhong Yang, Yuxi Wang, Taijing Wang, Jian Jiang, Catherine H. Botting, Huanting Liu, Qiang Chen, Jinliang Yang, James H. Naismith, Xiaofeng Zhu () and Lijuan Chen ()
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Jianhong Yang: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy and Cancer
Yuxi Wang: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy and Cancer
Taijing Wang: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy and Cancer
Jian Jiang: College of Life Science, Sichuan University
Catherine H. Botting: Biomedical Sciences Research Complex, University of St. Andrews
Huanting Liu: Biomedical Sciences Research Complex, University of St. Andrews
Qiang Chen: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy and Cancer
Jinliang Yang: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy and Cancer
James H. Naismith: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy and Cancer
Xiaofeng Zhu: College of Life Science, Sichuan University
Lijuan Chen: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy and Cancer

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: Abstract Molecules that alter the normal dynamics of microtubule assembly and disassembly include many anticancer drugs in clinical use. So far all such therapeutics target β-tubulin, and structural biology has explained the basis of their action and permitted design of new drugs. However, by shifting the profile of β-tubulin isoforms, cancer cells become resistant to treatment. Compounds that bind to α-tubulin are less well characterized and unexploited. The natural product pironetin is known to bind to α-tubulin and is a potent inhibitor of microtubule polymerization. Previous reports had identified that pironetin reacts with lysine-352 residue however analogues designed on this model had much lower potency, which was difficult to explain, hindering further development. We report crystallographic and mass spectrometric data that reveal that pironetin forms a covalent bond to cysteine-316 in α-tubulin via a Michael addition reaction. These data provide a basis for the rational design of α-tubulin targeting chemotherapeutics.

Date: 2016
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DOI: 10.1038/ncomms12103

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