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

• Published in: Nature communications Vol. 7; no. 1; p. 12103
• Main Authors: Yang, Jianhong, Wang, Yuxi, Wang, Taijing, Jiang, Jian, Botting, Catherine H., Liu, Huanting, Chen, Qiang, Yang, Jinliang, Naismith, James H., Zhu, Xiaofeng, Chen, Lijuan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.06.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 101/58; 631/45/612/1228; 631/57/2272; 631/67/1059/99; 631/80/128/1653; Escherichia coli; Humanities and Social Sciences; Mass Spectrometry; Microtubules - drug effects; Microtubules - metabolism; Molecular Targeted Therapy; multidisciplinary; Protein Conformation; Pyrones - chemistry; Pyrones - metabolism; Pyrones - pharmacology; Science; Science (multidisciplinary); Tubulin - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12103

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. Microtubule assembly and disassembly is the target of many anticancer therapies, with β-tubulin the most-frequent target. Here, the authors used biochemical and biophysical techniques to demonstrate pironetin binds to α-tubulin and thereby inhibits microtubule polymerization providing a basis for the rational design of novel anticancer drugs.