Pharmacological modulation of microtubule structure and its biological implications

2022/05/20 Atrio 800

Seminar

Pharmacological modulation of microtubule structure and its biological implications

Fernando Díaz

Pharmacological modulation of microtubule structure and its biological implications Tubulin behaves as a molecular switch regulated by guanine nucleotides. In the GTP-bound form, it is activated and capable of associating with the other subunits to form microtubules. In contrast, in its GDP-bound form, it is deactivated and tends to disassemble. The microtubule is formed by successive additions of GTP-bound active tubulin molecules. Nevertheless, the nucleotide hydrolysis site is not completed in the functional heterodimer and is only completed when the next tubulin unit binds, providing the necessary critical residue. This process makes the microtubule a to be filament that displays a chemical gradient from the positive end, where the new GTP-bound molecules are associated, to the negative end, where they are bound to GDP. This chemical gradient is reflected in subtle structural changes in the polymer structure that constitute structural cues to recruit the associated proteins. Given their importance in cell division, pharmacological regulation of these polymers is an obvious mechanism for cancer treatment. There are two types of modulators, those capable of activating the inactive GDP-bound tubulin, and those capable of inactivating the active tubulin. Recent work by our group has shown that microtubule stabilizers alter their structures, producing erroneous binding signals and altering microtubule function. This lecture focuses on the use of different drugs to structurally modulate microtubules and the molecular basis of the associated pharmacological effects.