The tubulin-bound conformation of paclitaxel: T-taxol vs "PTX-NY"

Nearly 35 years after its discovery and 11 years after FDA approval of paclitaxel (PTX) as a breakthrough anticancer drug, the 3-D structure of the agent bound to its beta-tubulin target was proposed to be T-Taxol. The latter bioactive form has recently been challenged by the Ojima group with a structure, "PTX-NY" ("REDOR Taxol"), in which the C-13 side chain is proposed to adopt a different conformation and an alternative hydrogen-bonding pattern in the tubulin binding site. Previously, the two conformers were compared to show that only T-Taxol fits the PTX-derived electron crystallographic density. That work has been extended by molecular mechanics and quantum chemical methods to reveal that the PTX-NY conformation is relatively less stable, on average, by 10-11 kcal/mol. In agreement with NMR studies, an 11 ns molecular dynamics treatment for PTX in an explicit water pool locates T-Taxol along the trajectory, but not PTX-NY. Docking of various PTX conformers into the electron crystallographic binding site of tubulin demonstrates that PTX-NY cannot be accommodated unless the pocket is reorganized in violation of the experimental constraints. Finally, analysis of the structures of T-Taxol and PTX-NY for their capacity to predict the existence of superpotent PTX analogues discloses that only the former forecasts such analogues, as now established by the T-Taxol-inspired synthesis of bridged taxanes. In sum, all empirical criteria support T-Taxol as the bound conformation of PTX on beta-tubulin in microtubules.