"Hydrophobic collapse" of taxol and Taxotere solution conformations in mixtures of water and organic solvent

Velde, David G. Vander; Georg, Gunda I.; Grunewald, Gary L.; Gunn, Christopher W.; Mitscher, Lester A.

doi:10.1021/ja00077a095

Cited by 151 publications

(108 citation statements)

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“…2a), was proposed as the bioactive one (17)(18)(19). Shortly thereafter, however, several laboratories argued in favor of the polar form (20)(21)(22) that juxtaposes the C-2 and C-3Ј benzamido side chains (Fig. 2b) (27).…”

Section: Discussionmentioning

confidence: 99%

“…Taxol combines a polar and rigid tetracyclic core with an equally polar set of four flexible side chains, containing 10 single bonds that contribute to the conformational flexibility of the molecule. Here we have explicitly considered 26 PTX conformers derived from x-ray crystal structures and from NMR nuclear Overhauser effect data of PTX and its derivatives (15)(16)(17)(18)(19)(20)(21)(22)(23)(24) and a large number of computergenerated conformers. The individual conformers were docked into the experimental density map of the TB-PTX complex.…”

Section: Methodsmentioning

confidence: 99%

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The binding conformation of Taxol in β-tubulin: A model based on electron crystallographic density

Snyder

Nettles²,

Cornett³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

363

396

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The chemotherapeutic drug Taxol is known to interact within a specific site on ␤-tubulin. Although the general location of the site has been defined by photoaffinity labeling and electron crystallography, the original data were insufficient to make an absolute determination of the bound conformation. We have now correlated the crystallographic density with analysis of Taxol conformations and have found the unique solution to be a T-shaped Taxol structure. This T-shaped or butterfly structure is optimized within the ␤-tubulin site and exhibits functional similarity to a portion of the B9-B10 loop in the ␣-tubulin subunit. The model provides structural rationalization for a sizeable body of Taxol structureactivity relationship data, including binding affinity, photoaffinity labeling, and acquired mutation in human cancer cells.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The binding conformation of Taxol in β-tubulin: A model based on electron crystallographic density

Snyder

Nettles²,

Cornett³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

363

396

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“…In yeast tubulin, A19 and G26 would significantly reduce the number of methylene groups available to interact with the phenyl ring. The imidazole ring of H227 lies between the C2 benzoyl phenyl and C3Ј benzamido phenyl rings in the T-Taxol model (16), interfering with the formation of the hydrophobically collapsed conformation of Taxol (32). H227 is also positioned between the C2 benzoyl phenyl and C3Ј benzamido phenyl rings in a model of Taxol binding proposed by Li et al (15).…”

Section: Discussionmentioning

confidence: 99%

Understanding tubulin–Taxol interactions: Mutations that impart Taxol binding to yeast tubulin

Gupta

Bode

Georg

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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115

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We have successfully used mutagenesis to engineer Taxol (paclitaxel) binding activity in Saccharomyces cerevisiae tubulin. Taxol, a successful antitumor agent, acts by promoting tubulin assembly and stabilizing microtubules. Several structurally diverse antimitotic compounds, including the epothilones, compete with Taxol for binding to mammalian microtubules, suggesting that Taxol and these compounds share an overlapping binding site. However, Taxol has no effect on tubulin or microtubules from S. cerevisiae, whereas epothilone does. After considering data on Taxol binding to mammalian tubulin and recent modeling studies, we have hypothesized that differences in five key amino acids are responsible for the lack of Taxol binding to yeast tubulin. After changing these amino acids to those found in mammalian brain tubulin, we observed Taxol-related activity in yeast tubulin comparable to that in mammalian tubulin. Importantly, this experimental system can be used to reveal tubulin interactions with Taxol, the epothilones, and other Taxol-like compounds.

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“…However, Taxol and its analogs exhibit different conformations in water and in organic polar solvent. 15 Furthermore, NMR analyses of molecular flexibility in the solution phase give rise to seven conformers, two of which (47% of the total population) correspond to the T-shaped conformation of PTX. 16 The T-shaped conformers superimpose well with the binding conformation of Taxol inˇ-tubulin.…”

Section: Methodsmentioning

confidence: 99%

“…16 The T-shaped conformers superimpose well with the binding conformation of Taxol inˇ-tubulin. 17,31 The structural information determined by solution NMR in nonpolar organic solvents 18,19 or mixture of polar and organic solvents 15 have significant differences 20,21 and we are thus motivated to investigate the molecular structure of Taxol in solid phase. In this work, we applied 13 C solid-state NMR spectroscopy to characterize the structure of Taxol in powder form.…”

Section: Methodsmentioning

confidence: 99%

Solid‐state NMR studies of the molecular structure of Taxol

Tzou

Chu

2006

Magnetic Reson in Chemistry

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"Hydrophobic collapse" of taxol and Taxotere solution conformations in mixtures of water and organic solvent

Cited by 151 publications

References 0 publications

The binding conformation of Taxol in β-tubulin: A model based on electron crystallographic density

The binding conformation of Taxol in β-tubulin: A model based on electron crystallographic density

Understanding tubulin–Taxol interactions: Mutations that impart Taxol binding to yeast tubulin

Solid‐state NMR studies of the molecular structure of Taxol

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