TAILIEUCHUNG - Báo cáo khoa học: Possible binding site for paclitaxel at microtubule pores

Taxanes and other microtubule-stabilizing agents comprise an important class of anticancer drugs. It is well known that taxanes act by binding to b-tubulin on the lumenal side of microtubules. However, experimental evi-dence obtained in recent years led to the hypothesis of an external site on the microtubule wall to which taxanes and other microtubule-stabilizing agents could bind before being internalized to their lumenal site. | ỊFEBS Journal Possible binding site for paclitaxel at microtubule pores Matteo Magnani1 Giorgio Maccari1 Jose M. Andreu2 J. F. Diaz2 and Maurizio Botta1 1 Department of Pharmaceuticaland ChemicalTechnology Faculty of Pharmacy University of Siena Italy 2 Centro de Investigaciones Biologicas Consejo Superior de Investigaciones Cientificas Madrid Spain Keywords conformationalanalysis hierarchical clustering microtubule paclitaxel Correspondence M. Botta Department of Pharmaceutical and ChemicalTechnology Faculty of Pharmacy University of Siena Via Aldo Moro 1 53100 Siena Italy Fax 39 05772 34333 Tel 39 05772 34306 E-mail botta@ Website http ricerca dip dfct Present address Siena Biotech SpA Italy Received 20 January 2009 revised 18 February 2009 accepted 3 March 2009 doi Taxanes and other microtubule-stabilizing agents comprise an important class of anticancer drugs. It is well known that taxanes act by binding to b-tubulin on the lumenal side of microtubules. However experimental evidence obtained in recent years led to the hypothesis of an external site on the microtubule wall to which taxanes and other microtubule-stabilizing agents could bind before being internalized to their lumenal site. In the present study different computational techniques were combined to explore the possible existence of an exposed and easily accessible binding site for microtubule-stabilizing agents on the outside of microtubules. The results obtained indicate that the conformational rearrangement of the H6-H7 hoop of b-tubulin can form a suitable pocket on the outer microtubule surface and that paclitaxel can efficaciously interact with this newly-proposed binding site. Microtubules are long filamentous tube-shaped protein polymers that are essential in all eukaryotic cells 1 . As key components of the cytoskeleton they are crucial in the development and maintenance of cell shape in the transport of vesicles mitochondria and other .

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