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Reference: Yang, J, Wang, Y, Wang, T et al., (2017). Pironetin reacts covalently with cysteine-316 of α-tubulin to destabilize microtubule. Nature Communications, 7, 12103.Citable link to this page:

 

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.

Publication status:PublishedPeer Review status:Peer reviewedVersion:Publisher's versionDate of acceptance:2016-05-27 Funder: National Natural Science Foundation of China   Funder: Chinese National Thousand Talents Program   Funder: Wellcome Trust Senior Investigator Award   Funder: Royal Society   Funder: Sichuan Province Thousand Talents Scheme   Funder: State Key Program of National Natural Science of China   Notes:© 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. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Bibliographic Details

Publisher: Nature Publishing Group

Publisher Website: https://www.nature.com/

Journal: Nature Communicationssee more from them

Publication Website: https://www.nature.com/ncomms

Volume: 7

Issue Date: 2017-06

pages:12103Identifiers

Doi: https://doi.org/10.1038/ncomms12103

Eissn: 2041-1723

Uuid: uuid:2e9eef89-b47c-4324-88c7-4af475b8aa8e

Urn: uri:2e9eef89-b47c-4324-88c7-4af475b8aa8e

Pubs-id: pubs:699015 Item Description

Type: journal-article;

Language: eng

Version: Publisher's versionKeywords: Journal Article

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Autor: Yang, J - - - Wang, Y - - - Wang, T - - - Jiang, J - - - Botting, CH - - - Liu, H - - - Chen, Q - - - Yang, J - - - Naismith, JH

Fuente: https://ora.ox.ac.uk/objects/uuid:2e9eef89-b47c-4324-88c7-4af475b8aa8e



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