期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 428, 期 15, 页码 2981-2988出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2016.06.023
关键词
microtubule-targeting agents; molecular mechanism of action; anticancer drug; protein-ligand interactions; X-ray crystallography
资金
- Ministerio de Economia y Competitividad [CTQ2014-52949-P]
- Conselleria d'Educacio and Investigacio, Cultura i Sport de la Generalitat Valenciana [PROMETEO 2013/027]
- Ministerio de Economia y Competitividad and Comunidad Autonoma de Madrid [BIO2013-42984-R, S2010/BMD-2457 BIPEDD2]
- Swiss National Science Foundation [310030B_138659, 31003A_166608]
Microtubule-targeting agents are among the most powerful drugs used in chemotherapy to treat cancer patients. Pironetin is a natural product that displays promising anticancer properties by binding to and potently inhibiting tubulin assembly into microtubules; however, its molecular mechanism of action remained obscure. Here, we solved the crystal structure of the tubulin-pironetin complex and found that the compound covalently binds to Cys316 of alpha-tubulin. The structure further revealed that pironetin perturbs the 17 loop and helix H8 of a-tubulin. Since both these elements are essential for establishing longitudinal tubulin contacts in microtubules, this result explains how pironetin inhibits the formation of microtubules. Together, our data define the molecular details of the pironetin binding site on alpha-tubulin and thus offer a promising basis for the rational design of pironetin variants with improved activity profiles. They further extend our knowledge on strategies evolved by natural products to target and perturb the microtubule cytoskeleton. (C) 2016 Elsevier Ltd. All rights reserved.
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