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.
Citation
Yang , J , Wang , Y , Wang , T , Jiang , J , Botting , C H , Liu , H , Chen , Q , Yang , J , Naismith , J H , Zhu , X & Chen , L 2016 , ' Pironetin reacts covalently with cysteine-316 of α-tubulin to destabilize microtubule ' , Nature Communications , vol. 7 , 12103 . https://doi.org/10.1038/ncomms12103
Publication
Nature Communications
Status
Peer reviewed
ISSN
2041-1723Type
Journal article
Rights
© The Author(s) 2016. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material.
Description
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).Collections
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