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Closed Access item Modulation of microtubule interprotofilament interactions by modified taxanes

Authors:Matesanz, Ruth
Rodríguez-Salarichs, Javier
Pera, Benet
Canales Mayordomo, María Ángeles
Andreu Morales, José Manuel
Jiménez-Barbero, Jesús
Bras, Wim
Nogales Ruiz, Aurora
Fang, Wei-shuo S.
Díaz, José Fernando
Issue Date:21-Dec-2011
Publisher:Elsevier
Citation:Biophysical Journal 101(12):2970-2980(2011)
Abstract:Microtubules assembled with paclitaxel and docetaxel differ in their numbers of protofilaments, reflecting modification of the lateral association between αβ-tubulin molecules in the microtubule wall. These modifications of microtubule structure, through a not-yet-characterized mechanism, are most likely related to the changes in tubulin-tubulin interactions responsible for microtubule stabilization by these antitumor compounds. We have used a set of modified taxanes to study the structural mechanism of microtubule stabilization by these ligands. Using small-angle x-ray scattering, we have determined how modifications in the shape and size of the taxane substituents result in changes in the interprotofilament angles and in their number. The observed effects have been explained using NMR-aided docking and molecular dynamic simulations of taxane binding at the microtubule pore and luminal sites. Modeling results indicate that modification of the size of substituents at positions C7 and C10 of the taxane core influence the conformation of three key elements in microtubule lateral interactions (the M-loop, the S3 β-strand, and the H3 helix) that modulate the contacts between adjacent protofilaments. In addition, modifications of the substituents at position C2 slightly rearrange the ligand in the binding site, modifying the interaction of the C7 substituent with the M-loop
Description:11 páginas, 4 figuras, 2 tablas -- PAGS nros. 2970-2980
Publisher version (URL):http://dx.doi.org/10.1016/j.bpj.2011.11.005
URI:http://hdl.handle.net/10261/50538
ISSN:0006-3495
E-ISSNmetadata.dc.identifier.doi = DOI:1542-0086
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