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Assembly of purified GDP-tubulin into microtubules induced by taxol and taxotere: reversibility, ligand stoichiometry, and competition.
Purified tubulin fully liganded to GDP at the exchangeable nucleotide binding site has been prepared by a new direct nucleotide exchange procedure, and this ligand-induced equilibrium microtubule assembly system dispenses with the requirement of a gamma-phosphate-metal cation ligand bound at the nucleotide site for tubulin to be active.
The microtubule stabilizing agent laulimalide does not bind in the taxoid site, kills cells resistant to paclitaxel and epothilones, and may not require its epoxide moiety for activity.
Laulimalide is a cytotoxic natural product that stabilizes microtubules. The compound enhances tubulin assembly, and laulimalide is quantitatively comparable to paclitaxel in its effects on the…
Thermodynamics of ligand-induced assembly of tubulin.
It is proposed that the taxoid binding changes the conformation of GDP-tubulin from inactive to active, allowing productive binding and elongation at the microtubule end, and is particularly attractive to think of taxoids as double-sided ligands, which bind to tubulin at the microscopic end and participate in a lateral contact interface with the newly added tubulin molecule.
Interaction of epothilone analogs with the paclitaxel binding site: relationship between binding affinity, microtubule stabilization, and cytotoxicity.
Insights into the Distinct Mechanisms of Action of Taxane and Non-Taxane Microtubule Stabilizers from Cryo-EM Structures.
Control of the Structural Stability of the Tubulin Dimer by One High Affinity Bound Magnesium Ion at Nucleotide N-site*
- M. Menéndez, G. Rivas, J. Díaz, J. Andreu
- Biology, ChemistryThe Journal of Biological Chemistry
- 2 January 1998
The tubulin properties described would be simply explained if the N-site and the colchicine site are at the α-β dimerization interface, consistent with the known functional role of the E nucleotide γ-phosphate and coordinated cation controlling microtubule stability.
TRAPPII regulates exocytic Golgi exit by mediating nucleotide exchange on the Ypt31 ortholog RabERAB11
Evidence obtained by exploiting hypA1-mediated destabilization of HypATrs120/HypCTrs130/Trs65 assembly onto the TRAPPI core indicates that these subunits sculpt a second RAB binding site on TRAPP apparently independent from that for RabORAB1, which would explain TRAPPII in vitro activity on two RABs.
A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs
- A. Prota, K. Bargsten, M. Steinmetz
- Biology, ChemistryProceedings of the National Academy of Sciences
- 11 August 2014
The results delineate a distinct molecular mechanism of action for the inhibition of microtubule assembly by clinically relevant agents, and provide a structural basis for the rational design of potent microtubules-destabilizing agents, thus opening opportunities for the development of next-generation ADCs for the treatment of cancer.
Molecular Recognition of Taxol by Microtubules
- J. Díaz, Rik Strobe, Y. Engelborghs, A. A. Souto, J. Andreu
- Chemistry, BiologyThe Journal of Biological Chemistry
- 25 August 2000
The kinetic scheme and reaction rates of binding to microtubules of two fluorescent taxoids and the results indicate that the Taxol binding site is directly accessible, in contrast with its location at lumen in the current model of micro Tubules.
The nucleotide switch of tubulin and microtubule assembly: a polymerization-driven structural change.
From these and the biochemical properties of tubulin, the new concept emerges that, contrary to what was thought, unassembled tubulin-GTP is in the inactive, curved conformation and it is driven into the straight microtubule conformation by the assembly contacts; binding of the GTP gamma-phosphate only lowers the free energy difference between the curved and straight forms.