Modeling the Yew Tree Tubulin and a Comparison of its Interaction with Paclitaxel to Human Tubulin
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To explore possible ways in which yew tree tubulin is naturally resistant to paclitaxel. While the yew produces a potent cytotoxin, paclitaxel, it is immune to paclitaxel’s cytotoxic action.
Tubulin sequence data for plant species were obtained from Alberta 1000 Plants Initiative. Sequences were assembled with Trinity de novo assembly program and tubulin identified. Homology modeling using MODELLER software was done to generate structures for yew tubulin. Molecular dynamics simulations and molecular mechanics Poisson–Boltzmann calculations were performed with the Amber package to determine binding affinity of paclitaxel to yew tubulin. ClustalW2 program and PHYLIP package were used to perform phylogenetic analysis on plant tubulin sequences.
We specifically analyzed several important regions in tubulin structure: the high-affinity paclitaxel binding site, as well as the intermediate binding site and microtubule nanopores. Our analysis indicates that the high-affinity binding site contains several substitutions compared to human tubulin, all of which reduce the binding energy of paclitaxel.
The yew has achieved a significant reduction of paclitaxel’s affinity for its tubulin by utilizing several specific residue changes in the binding pocket for paclitaxel.
KEY WORDSchemotherapy nanopores paclitaxel tubulin yew tree
1000 plants initiative
basic local alignment search tool
molecular mechanics Poisson–Boltzmann surface area
open reading frames
protein data bank
root mean square deviation
ACKNOWLEDGMENTS AND DISCLOSURES
J.A.T. acknowledges support for this research from the Alberta Cancer Foundation, Alberta Advanced Education and Technology, the Allard Foundation, the Canadian Breast Cancer Foundation, and the National Sciences and Engineering Research Council of Canada (NSERC Canada). T.J.A.C. acknowledges funding support for this research from NSERC Canada. G.K.S.W. acknowledges Alberta Advanced Education and Technology, Genome Alberta, Alberta Innovates Tech Futures iCORE, Musea Ventures, and BGI-Shenzhen for the funding of the Alberta 1000 Plants Initiative.
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