The Bound Conformation of Microtubule-Stabilizing Agents, Part 2; for Part 1 see: J. Jiménez-Barbero, A. Canales, P. T. Northcote, R. M. Buey, J. M. Andreu, J. F. Díaz, J. Am. Chem. Soc.2006, 128, 8757–8765.
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Full Paper
The Bound Conformation of Microtubule-Stabilizing Agents: NMR Insights into the Bioactive 3D Structure of Discodermolide and Dictyostatin†
Article first published online: 30 APR 2008
DOI: 10.1002/chem.200800039
Copyright © 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Additional Information
How to Cite
Canales, A., Matesanz, R., Gardner, Nicola M., Andreu, J., Paterson, I., Díaz, J. Fernando. and Jiménez-Barbero, J. (2008), The Bound Conformation of Microtubule-Stabilizing Agents: NMR Insights into the Bioactive 3D Structure of Discodermolide and Dictyostatin. Chem. Eur. J., 14: 7557–7569. doi: 10.1002/chem.200800039
- †
Publication History
- Issue published online: 25 AUG 2008
- Article first published online: 30 APR 2008
- Manuscript Received: 9 JAN 2008
Funded by
- Ministery of Education and Science of Spain
- Comunidad Autonoma de Madrid. Grant Numbers: CTQ2006-10874-C02-01, BIO2007-61336, S-BIO-0214-2006
Keywords:
- anticancer agents;
- conformation analysis;
- microtubules;
- molecular modeling;
- molecular recognition
Abstract
A protocol based on a combination of NMR experimental data with molecular mechanics calculations and docking procedures has been employed to determine the microtubule-bound conformation of two microtubule-stabilizing agents, discodermolide (DDM) and dictyostatin (DCT). The data indicate that tubulin in assembled microtubules recognizes DDM through a conformational selection process, with minor changes in the molecular skeleton between the major conformer in water solution and that bound to assembled microtubules. For DCT, the deduced bound geometry presents some key conformation differences around certain torsion angles, with respect to the major conformer in solution, and still displays mobility even when bound. The bound conformer of DCT resembles that of DDM and provides very similar contacts with the receptor. Competition experiments indicate that both molecules compete with the taxane-binding site. A model of the binding mode of DDM and DCT to tubulin is proposed.