T-taxol conformation

T-Taxol is a proposal for the bioactive conformation of paclitaxel (PTX) derived from fitting ligand conformations to the electron crystallographic (EC) density. Although confirmed by a number of studies, some structural ambiguities based on the interpretation of two solid-state REDOR C-13-F-19 distances in a fluorinated PTX derivative remain. An evaluation of the static and dynamic properties of the PTX-tubulin complex shows that small 6-12 degrees variations in calculated torsions and a justifiable increase of the REDOR distance error to a >=+/- 0.7 angstrom readily resolves key discrepancies around T-Taxol's service as the bioactive conformation. In addition, conformational analysis reveals a range of C-13-F-19 separations compatible with the REDOR measurements suggesting that the present PTX REDOR distances may not provide a precise model for bioactive, tubulin-bound bridged taxanes. In addition, we show that New York-Taxol (PTX-NY), a recently proposed alternative to T-Taxol, is incompatible with both the EC density and the activity of a highly active series of bridged taxanes.