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

Jianhong Yang; Yuxi Wang; Taijing Wang; Jian Jiang; Catherine Helen Botting; Huanting Liu; Qiang Chen; Jingliang Yang; James Henderson Naismith; Xiaofeng Zhu; Lijuan Chen

doi:10.1038/ncomms12103

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

Jianhong Yang, Yuxi Wang, Taijing Wang, Jian Jiang, Catherine Helen Botting, Huanting Liu, Qiang Chen, Jingliang Yang, James Henderson Naismith, Xiaofeng Zhu, Lijuan Chen

Research output: Contribution to journal › Article › peer-review

Abstract

Molecules which 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.  

Original language	English
Article number	12103
Number of pages	9
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12103
Publication status	Published - 30 Jun 2016

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Cite this

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title = "Pironetin reacts covalently with cysteine-316 of α-tubulin to destabilize microtubule",

abstract = "Molecules which 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.  ",

author = "Jianhong Yang and Yuxi Wang and Taijing Wang and Jian Jiang and Botting, \{Catherine Helen\} and Huanting Liu and Qiang Chen and Jingliang Yang and Naismith, \{James Henderson\} and Xiaofeng Zhu and Lijuan Chen",

note = "This work was funded by grants to C.L. from the National Natural Science Foundation of  China (81373283 and U1402222). J.H.N. is supported as an award holder of Chinese National  Thousand Talents Program, Wellcome Trust Senior Investigator Award (WT100209MA) and  Royal Society Wolfson Merit Award. X.Z. is supported by Sichuan Province Thousand Talents  Scheme in China and the State Key Program of National Natural Science of China (21534008).",

year = "2016",

month = jun,

day = "30",

doi = "10.1038/ncomms12103",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

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T1 - Pironetin reacts covalently with cysteine-316 of α-tubulin to destabilize microtubule

AU - Yang, Jianhong

AU - Wang, Yuxi

AU - Wang, Taijing

AU - Jiang, Jian

AU - Botting, Catherine Helen

AU - Liu, Huanting

AU - Chen, Qiang

AU - Yang, Jingliang

AU - Naismith, James Henderson

AU - Zhu, Xiaofeng

AU - Chen, Lijuan

N1 - This work was funded by grants to C.L. from the National Natural Science Foundation of  China (81373283 and U1402222). J.H.N. is supported as an award holder of Chinese National  Thousand Talents Program, Wellcome Trust Senior Investigator Award (WT100209MA) and  Royal Society Wolfson Merit Award. X.Z. is supported by Sichuan Province Thousand Talents  Scheme in China and the State Key Program of National Natural Science of China (21534008).

PY - 2016/6/30

Y1 - 2016/6/30

N2 - Molecules which 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.  

AB - Molecules which 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.  

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U2 - 10.1038/ncomms12103

DO - 10.1038/ncomms12103

M3 - Article

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 12103

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

Abstract

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Wolfson Merit Award: Characterising membrane proteins by biophysical methods

Transport and Polymerisation INV Award: Transport and polymerisation of bacterial polysaccharides

5JQG An apo tubulin-RB-TTL complex structure used for side-by-side comparison

5FNV a new complex structure of tubulin with an alpha-beta unsaturated lactone

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

Abstract

UN SDGs

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Other files and links

Fingerprint

Projects

Wolfson Merit Award: Characterising membrane proteins by biophysical methods

Transport and Polymerisation INV Award: Transport and polymerisation of bacterial polysaccharides

Datasets

5JQG An apo tubulin-RB-TTL complex structure used for side-by-side comparison

5FNV a new complex structure of tubulin with an alpha-beta unsaturated lactone

Cite this