Modeling the interaction of paclitaxel with beta-tubulin.
The natural product cytotoxic agent, paclitaxel, partly induces cell death through its ability to disrupt mitosis by binding to the microtubule protein beta-tubulin. Structural characterization of the paclitaxel-beta-tubulin complex, a first stage in the design of new antimitotics, has been complicated by contradictory observations obtained from different experimental techniques [electron crystallography, fluorescence resonance energy transfer (FRET), and photo-affinity labeling (PAL)] used to examine the complex. In this study we have used a range of molecular modeling techniques including restrained conformational searching and computer-assisted docking to propose that these contradictions may be resolved by the hypothesis that the nature of the interaction of paclitaxel with beta-tubulin depends on the physical form of the tubulin examined. In particular, our analysis identified a binding mode that is consistent with available data for the interaction of paclitaxel with beta-tubulin in polymerized tubulin or microtubules. This orientation is characterized by an alternate conformation (inverted orientation of side chains) and inverted orientation of the taxane core of paclitaxel within its tubulin binding site compared with the electron crystallographic structure. The proposed structure, however, is only marginally consistent with electron crystallographic data for the interaction of paclitaxel with beta-tubulin in Zn-induced tubulin sheets. Similarly, the electron crystallographic structure shows poor correlation with FRET, solid-state NMR, and some observed SAR relationships for paclitaxel interacting with polymerized tubulin or microtubules. These observations suggest to us that the interaction of paclitaxel with Zn-induced tubulin sheets may not reflect paclitaxel's interaction with tubulin in microtubules and hence may not be an appropriate guide for rational drug design programs.
Ivery
Michael T G
MT
Faculty of Pharmacy, University of Sydney, N.S.W. 2006, Australia. michaeli@pharm.usyd.edu.au
Le
Tuyet
T
D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry*; D001665:Binding Sites; D003461:Crystallography; D015195:Drug Design; D008870:Microtubules / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D017239:Paclitaxel / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry*
D000972:Antineoplastic Agents, Phytogenic; D014404:Tubulin; D017239:Paclitaxel