Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2010 Apr;67(7):1089-104.
doi: 10.1007/s00018-009-0245-6. Epub 2010 Jan 28.

Microtubule targeting agents: from biophysics to proteomics

Affiliations
Review

Microtubule targeting agents: from biophysics to proteomics

D Calligaris et al. Cell Mol Life Sci. 2010 Apr.

Abstract

This review explores various aspects of the interaction between microtubule targeting agents and tubulin, including binding site, affinity, and drug resistance. Starting with the basics of tubulin polymerization and microtubule targeting agent binding, we then highlight how the three-dimensional structures of drug-tubulin complexes obtained on stabilized tubulin are seeded by precise biological and biophysical data. New avenues opened by thermodynamics analysis, high throughput screening, and proteomics for the molecular pharmacology of these drugs are presented. The amount of data generated by biophysical, proteomic and cellular techniques shed more light onto the microtubule-tubulin equilibrium and tubulin-drug interaction. Combining these approaches provides new insight into the mechanism of action of known microtubule interacting agents and rapid in-depth characterization of next generation molecules targeting the interaction between microtubules and associated modulators of their dynamics. This will facilitate the design of improved and/or alternative chemotherapies targeting the microtubule cytoskeleton.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Microtubule polymerization phases. Microtubules grow by addition of GTP-tubulin subunits. After their incorporation, subunits are hydrolyzed to become GDP-tubulin. The straight tubulin conformation within the microtubule lattice is stabilized by a ‘cap’ of tubulin-GTP subunits. Closure of the terminal sheet structure generates a metastable, blunt-ended microtubule intermediate, which might pause, undergo further growth, or switch to the depolymerization phase possibly by loss of the GTP-tubulin at the end. GDP-tubulin is free to splay out and the microtubule rapidly shrinks. Microtubules can transition from growth to shrinking phases called catastrophes. Protection of microtubules from shrinking by adding GTP-tubulin at the tip of microtubule is referred to as rescue
Fig. 2
Fig. 2
Structure of microtubule destabilizers and stabilizers
Fig. 3
Fig. 3
Tubulin binding site of MTAs
Fig. 4
Fig. 4
MALDI-MS/MS and MALDI-IMS-MS/MS whole body imaging of rats dosed at 6 mg/kg IV with vinblastine. Distribution of the precursor ion m/z 811.4 (vinblastine) and production m/z 751 (vinblastine dissociation product) is shown. Comparison of a m/z 811 and b m/z 811-751 images obtained using MALDI-IMS-MS/MS and conventional MALDI-MS/MS clearly demonstrate the advantages of ion mobility separation within MALDI xenobiotic imaging. The main difference observed is indicated; the distribution of the ions of interest within the renal pelvis. White contrast indicates vinblastine concentration. c Whole body autoradiograph showing the distribution of 3H in a 1-h post-dose rat dosed with 6 mg/kg IV 3H vinblastine, confirming the distribution observed with MALDI-IMS-MS/MS. Reprinted with the authorization of the American Chemical Society

Similar articles

Cited by

References

    1. Bryan J, Wilson L. Are cytoplasmic microtubules heteropolymers? Proc Natl Acad Sci USA. 1971;68:1762–1766. - PMC - PubMed
    1. Akhmanova A, Steinmetz MO. Tracking the ends: a dynamic protein network controls the fate of microtubule tips. Nat Rev Mol Cell Biol. 2008;9:309–322. - PubMed
    1. Nogales E, Wang HW. Structural intermediates in microtubule assembly and disassembly: how and why? Curr Opin Cell Biol. 2006;18:179–184. - PubMed
    1. Ballestrem C, Magid N, Zonis J, Shtutman M, Bershadsky A. Interplay between the actin cytoskeleton, focal adhesions, and microtubules. In: Ridley A, Peckham M, Clark P, editors. Cell motility. From molecules to organisms. Chichester: Wiley; 2004. pp. 75–99.
    1. Vasiliev JM, Gelfand IM, Domnina LV, Ivanova OY, Komm SG, Olshevskaja LV. Effect of colcemid on the locomotory behaviour of fibroblasts. J Embryol Exp Morphol. 1970;24:625–640. - PubMed