title: The T-Taxol conformation.
abstract: 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 (13)C-(19)F 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 > or = +/-0.7 A readily resolves key discrepancies around T-Taxol's service as the bioactive conformation. In addition, conformational analysis reveals a range of (13)C-(19)F 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.
authors.affiliation: Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
authors.forename: Ana A
authors.initials: AA
authors.lastname: Alcaraz
authors.forename: Anil K
authors.initials: AK
authors.lastname: Mehta
authors.forename: Scott A
authors.initials: SA
authors.lastname: Johnson
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
mesh_terms: D001665:Binding Sites; D003461:Crystallography; D000077143:Docetaxel; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D017239:Paclitaxel / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000737:chemistry / Q000187:drug effects
chemical_list: D008024:Ligands; D043823:Taxoids; D014404:Tubulin; C510300:nonataxel; D000077143:Docetaxel; D017239:Paclitaxel