The binding mode of epothilone A on alpha,beta-tubulin by electron crystallography.
The structure of epothilone A, bound to alpha,beta-tubulin in zinc-stabilized sheets, was determined by a combination of electron crystallography at 2.89 angstrom resolution and nuclear magnetic resonance-based conformational analysis. The complex explains both the broad-based epothilone structure-activity relationship and the known mutational resistance profile. Comparison with Taxol shows that the longstanding expectation of a common pharmacophore is not met, because each ligand exploits the tubulin-binding pocket in a unique and independent manner.
Nettles
James H
JH
Molecular and Systems Pharmacology, Emory University, Atlanta, GA 30322, USA.
Li
Huilin
H
Cornett
Ben
B
Krahn
Joseph M
JM
Snyder
James P
JP
Downing
Kenneth H
KH
D001665:Binding Sites; D003461:Crystallography; D018360:Crystallography, X-Ray; D034261:Epothilones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D017239:Paclitaxel / Q000378:metabolism; D011487:Protein Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D034261:Epothilones; D008024:Ligands; D014404:Tubulin; C093787:epothilone A; D017239:Paclitaxel