Taxol exploits molecular switches within tubulin to stabilize microtubules
Year: 2026
Type: preprint
Abstract: Microtubules are dynamic filaments of tubulin heterodimers that comprise an essential part of the eukaryotic cytoskeleton 1 . The nucleotide state of tubulin controls microtubule dynamics: stable GTP-microtubules favor polymerization, whereas unstable GDP-microtubules drive depolymerization 2 . Anticancer compounds such as Taxol (paclitaxel) target microtubule dynamicity by preventing microtubule depolymerization 3,4 . Despite decades of work, the molecular basis of microtubule dynamics remains poorly defined. Using cryo-EM, we determined ∼2.2 Å structures of human microtubules in GTP-like (GMPCPP) and GDP states. Comparison of these two states revealed switch-like structural changes as tubulins transition from the pre-hydrolysis (GMPCPP) to the post-hydrolysis (GDP) state. Additional structure determination of Taxol-bound microtubules at ∼2.2 Å showed that Taxol binding converts the microtubule lattice into a pre-hydrolysis state by reversing the structural switches flipped during GTP hydrolysis. Focusing our analysis on the microtubule seam shows that the pre-hydrolysis conformation of GMPCPP or Taxol-GDP exhibits favorable lateral interactions at the seam, with lattice deformations clearly visible at the GDP seam. Together, our data show the existence of structural switches in tubulin that are coupled to the nucleotide state and are exploited by Taxol to stabilize microtubules into a pre-hydrolysis-like state. (191 words)
Institutions: University of Michigan, Vanderbilt University
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
Awards: Compute Cluster for in vitro and in situ Analysis of Molecular Machines, Dynamic Regulation of the Actin Filament Barbed End, Mechanisms of kinesin motor protein inhibition, Kinesin Motors and Microtubule-based Trafficking, Mechanisms of dynein regulation, Biophysical Principles of Microtubule Dynamics, Cellular and Molecular Biology at Michigan
OpenAlex ID: W7161648108