About the Project
In this project, the student will express different tubulin isotypes using a recombinant system to generate isotype-pure tubulin from human and Drosophila, and assess their sensitivity and affinity to known tubulin drugs using in vitro reconstitution and fluorescence anisotropy. The student will also have the opportunity to determine the cryo-EM structure of isotype-specific microtubules using our in-house EM facilities and study the mechanical properties of these isotype-pure microtubules, using AFM.
Using the chemical expertise of the Hulme lab, the student will then synthesize and optimize nocodazole derived compounds, and macrocyclic compounds targeting the maytansine sub-site[2,3] to selectively target specific isotypes. Computational approaches will be used to optimize the molecules. The student will first characterise the compounds biophysically with purified tubulin and test its activity on microtubule dynamics and assembly in vitro. From this work, the student will be able to hypothesize how drugs may fail to work in certain cell types, while the results will offer them opportunities to improve small molecule inhibitors based on isotype specificity and expression patterns.
This project enables a motivated Ph.D. student to apply chemistry, physics, cell biology, biochemistry and in vitro reconstitution assays to investigate the molecular properties of tubulin isotypes. These results will have strong implications for our understanding of cytoskeleton biology and the synthesis and optimization of macrocyclic drugs for personalized medicine, where microtubule-targeting drugs are often used to treat cancers and in agriculture, where microtubule-targeting drugs are used as pesticides.
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 Self-assembly of Disorazole C1 Using a One-pot Alkyne Metathesis Homodimerization Strategy: K. J. Ralston, H. C. Ramstadius, R. C. Brewster, H. S. Niblock, A. N. Hulme, Angew. Chem. Int. Ed. 2015. 54:7086-7090.
 A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin: G. Menchon, A. E. Prota, D. Lucena-Agell, P. Bucher, R. Jansen, H. Irschik, R. Müller, I. Paterson, J. F. Díaz, K.-H. Altmann, M. O. Steinmetz, Nature Commun. 2018. 9: 2106.
 Human β-Tubulin Isotypes Can Regulate Microtubule Protofilament Number and Stability: S. C. Ti, G. M. Alushin, T. M. Kapoor. Dev Cell. 2018. 47:175-190.
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