title: Pironetin reacts covalently with cysteine-316 of α-tubulin to destabilize microtubule.
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.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy and Cancer, Chengdu 610041, China.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy and Cancer, Chengdu 610041, China.
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy and Cancer, Chengdu 610041, China.
authors.forename: Taijing
authors.initials: T
authors.lastname: Wang
authors.affiliation: College of Life Science, Sichuan University, Chengdu 610064, China.
authors.forename: Jian
authors.identifier: 0000-0002-1922-7489
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Biomedical Sciences Research Complex, University of St. Andrews, St Andrews KY16 9ST, UK.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Botting
authors.affiliation: Biomedical Sciences Research Complex, University of St. Andrews, St Andrews KY16 9ST, UK.
authors.forename: Huanting
authors.initials: H
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy and Cancer, Chengdu 610041, China.
authors.forename: Qiang
authors.identifier: 0000-0002-2398-4482
authors.initials: Q
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy and Cancer, Chengdu 610041, China.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy and Cancer, Chengdu 610041, China.|Biomedical Sciences Research Complex, University of St. Andrews, St Andrews KY16 9ST, UK.
authors.forename: James H
authors.initials: JH
authors.lastname: Naismith
authors.affiliation: College of Life Science, Sichuan University, Chengdu 610064, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy and Cancer, Chengdu 610041, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
mesh_terms: D004926:Escherichia coli; D013058:Mass Spectrometry; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D011487:Protein Conformation; D011753:Pyrones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism*
chemical_list: D011753:Pyrones; D014404:Tubulin; C088446:pironetin