Zampanolide, a Potent New Microtubule-Stabilizing Agent, Covalently Reacts with the Taxane Luminal Site in Tubulin α,β-Heterodimers and Microtubules

被引：78

作者：

Field, Jessica J. ^{[2
]}

Pera, Benet ^{[1
]}

Calvo, Enrique ^{[4
]}

Canales, Angeles ^{[1
,5
]}

Zurwerra, Didier ^{[6
]}

Trigili, Chiara ^{[1
]}

Rodriguez-Salarichs, Javier ^{[1
,7
]}

Matesanz, Ruth ^{[1
]}

Kanakkanthara, Arun ^{[2
]}

Wakefield, St John ^{[8
]}

Singh, A. Jonathan ^{[3
]}

Jimenez-Barbero, Jesus ^{[1
]}

Northcote, Peter ^{[3
]}

Miller, John H. ^{[2
]}

Antonio Lopez, Juan ^{[4
]}

Hamel, Ernest ^{[9
]}

Barasoain, Isabel ^{[1
]}

Altmann, Karl-Heinz ^{[6
]}

Fernando Diaz, Jose ^{[1
]}

机构：

[1] CSIC, Ctr Invest Biol, Madrid 28040, Spain

[2] Victoria Univ Wellington, Sch Biol Sci, Wellington 6012, New Zealand

[3] Victoria Univ Wellington, Sch Chem & Phys Sci, Wellington 6012, New Zealand

[4] Ctr Nacl Invest Cardiovasc, Unidad Prote, Madrid 28029, Spain

[5] Univ Complutense Madrid, Fac Ciencias Quim, E-28040 Madrid, Spain

[6] Swiss Fed Inst Technol, Dept Chem & Appl Biosci, Inst Pharmaceut Sci, Zurich, Switzerland

[7] Ctr Estudios Avanzados Cuba, Havana, Cuba

[8] Wellington Sch Med & Hlth Sci, Dept Pathol, Wellington 6021, New Zealand

[9] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA

来源：

CHEMISTRY & BIOLOGY | 2012年 / 19卷 / 06期

关键词：

HIGH-AFFINITY; MOLECULAR RECOGNITION; CYTOTOXIC MACROLIDE; BOUND CONFORMATION; BINDING-SITES; TAXOID SITE; NMR; PACLITAXEL; EPOTHILONE; LIGAND;

D O I：

10.1016/j.chembiol.2012.05.008

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Zampanolide and its less active analog dactylolide compete with paclitaxel for binding to microtubules and represent a new class of microtubule-stabilizing agent (MSA). Mass spectrometry demonstrated that the mechanism of action of both compounds involved covalent binding to beta-tubulin at residues N228 and H229 in the taxane site of the microtubule. Alkylation of N228 and H229 was also detected in alpha,beta-tubulin dimers. However, unlike cyclostreptin, the other known MSA that alkylates beta-tubulin, zampanolide was a strong MSA. Modeling the structure of the adducts, using the NMR-derived dactylolide conformation, indicated that the stabilizing activity of zampanolide is likely due to interactions with the M-loop. Our results strongly support the existence of the luminal taxane site of microtubules in tubulin dimers and suggest that microtubule nucleation induction by MSAs may proceed through an allosteric mechanism.

引用

页码：686 / 698

页数：13

共 3 条

[1] Enantioselective Total Synthesis of (-)-Zampanolide, a Potent Microtubule-Stabilizing Agent
Ghosh, Arun K.
Cheng, Xu
ORGANIC LETTERS, 2011, 13 (15) : 4108 - 4111
[2] Tubulin assembly, taxoid site binding, and cellular effects of the microtubule-stabilizing agent dictyostatin
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Edler, MC
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