Interactions of halichondrin B and eribulin with tubulin

Ruoli Bai, Tam Luong Nguyen, James C. Burnett, Onur Atasoylu, Murray H G Munro, George Pettit, Amos B. Smith, Rick Gussio, Ernest Hamel

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Compounds that modulate microtubule dynamics include highly effective anticancer drugs, leading to continuing efforts to identify new agents and improve the activity of established ones. Here, we demonstrate that [ 3H]-labeled halichondrin B (HB), a complex, sponge-derived natural product, is bound to and dissociated from tubulin rapidly at one binding site per αβ-heterodimer, with an apparent Kd of 0.31 μM. We found no HB-induced aggregation of tubulin by high-performance liquid chromatography, even following column equilibration with HB. Binding of [ 3H]HB was competitively inhibited by a newly approved clinical agent, the truncated HB analogue eribulin (apparent Ki, 0.80 μM) and noncompetitively by dolastatin 10 and vincristine (apparent Ki's, 0.35 and 5.4 μM, respectively). Our earlier studies demonstrated that HB inhibits nucleotide exchange on β-tubulin, and this, together with the results presented here, indicated the HB site is located on β-tubulin. Using molecular dynamics simulations, we determined complementary conformations of HB and β-tubulin that delineated in atomic detail binding interactions of HB with only β-tubulin, with no involvement of the α-subunit in the binding interaction. Moreover, the HB model served as a template for an eribulin binding model that furthered our understanding of the properties of eribulin as a drug. Overall, these results established a mechanistic basis for the antimitotic activity of the halichondrin class of compounds.

Original languageEnglish (US)
Pages (from-to)1393-1404
Number of pages12
JournalJournal of Chemical Information and Modeling
Volume51
Issue number6
DOIs
StatePublished - Jun 27 2011

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

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    Bai, R., Nguyen, T. L., Burnett, J. C., Atasoylu, O., Munro, M. H. G., Pettit, G., Smith, A. B., Gussio, R., & Hamel, E. (2011). Interactions of halichondrin B and eribulin with tubulin. Journal of Chemical Information and Modeling, 51(6), 1393-1404. https://doi.org/10.1021/ci200077t