Skip NavigationSkip to Content
Return Return to Search Results

Cyclostreptin binds covalently to microtubule pores and lumenal taxoid binding sites

  1. Author:
    Buey, R. M.
    Calvo, E.
    Barasoain, I.
    Pineda, O.
    Edler, M. C.
    Matesanz, R.
    Cerezo, G.
    Vanderwal, C. D.
    Day, B. W.
    Sorensen, E. J.
    Lopez, J. A.
    Andreu, J. M.
    Hamel, E.
    Diaz, J. F.

  2. Author Address

    CSIC, Ctr Invest Biol, E-28040 Madrid, Spain. Ctr Nacl Invest Cardiovasc, Unidad Proteom, Madrid 28029, Spain. Univ Barcelona, Fac Quim, Dept Quim Organ, E-08028 Barcelona, Spain. NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. Univ Calif Irvine, Dept Chem, Irvine, CA 92697 USA. PharmaMar SA, Colmenar Viejo 28770, Spain. Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15261 USA. Princeton Univ, Dept Chem, Princeton, NJ 08544 USA.;Diaz, JF, CSIC, Ctr Invest Biol, Ramiro Maeztu 9, E-28040 Madrid, Spain.;fer@cib.csic.es
    1. Year: 2007
    2. Date: Feb
  2. Journal: Nature Chemical Biology
    1. 3
    2. 2
    3. Pages: 117-125
  4. Type of Article: Article
  5. ISSN: 1552-4450
  1. Abstract:

    Cyclostreptin ( 1), a natural product from Streptomyces sp. 9885, irreversibly stabilizes cellular microtubules, causes cell cycle arrest, evades drug resistance mediated by P- glycoprotein in a tumor cell line and potently inhibits paclitaxel binding to microtubules, yet it only weakly induces tubulin assembly. In trying to understand this paradox, we observed irreversible binding of synthetic cyclostreptin to tubulin. This results from formation of covalent crosslinks to beta- tubulin in cellular microtubules and microtubules formed from purified tubulin in a 1: 1 total stoichiometry distributed between Thr220 ( at the outer surface of a pore in the microtubule wall) and Asn228 ( at the lumenal paclitaxel site). Unpolymerized tubulin was only labeled at Thr220. Thus, the pore region of beta- tubulin is an undescribed binding site that ( i) elucidates the mechanism by which taxoid-site compounds reach the kinetically unfavorable lumenal site and ( ii) explains how taxoid-site drugs induce microtubule formation from dimeric and oligomeric tubulin.

    See More

  1. Keywords:

External Sources

  1. View Full Text
  2. DOI: 10.1038/nchembio853
  3. View record in Web of Science®
  4. WOS: 000243685800016

Library Notes

  1. No notes added.
NCI at Frederick

You are leaving a government website.

This external link provides additional information that is consistent with the intended purpose of this site. The government cannot attest to the accuracy of a non-federal site.

Linking to a non-federal site does not constitute an endorsement by this institution or any of its employees of the sponsors or the information and products presented on the site. You will be subject to the destination site's privacy policy when you follow the link.

ContinueCancel