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Vol. 15, Issue 4, 1960-1968, April 2004

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Dinitroanilines Bind -Tubulin to Disrupt Microtubules

Naomi S. Morrissette ^* , Arpita Mitra  ^||, David Sept  ^||, and L. David Sibley ^*

^* Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110; Department of Chemical Engineering, Washington University School of Medicine, St. Louis, Missouri 63110; Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, Missouri 63110; and ^|| Department of Center for Computational Biology, Washington University School of Medicine, St. Louis, Missouri 63110

Submitted July 25, 2003; Revised January 7, 2004; Accepted January 7, 2004
Monitoring Editor: Lawrence Goldstein

Protozoan parasites are remarkably sensitive to dinitroanilines such as oryzalin, which disrupt plant but not animal microtubules. To explore the basis of dinitroaniline action, we isolated 49 independent resistant Toxoplasma gondii lines after chemical mutagenesis. All 23 of the lines that we examined harbored single point mutations in -tubulin. These point mutations were sufficient to confer resistance when transfected into wild-type parasites. Several mutations were in the M or N loops, which coordinate protofilament interactions in the microtubule, but most of the mutations were in the core of -tubulin. Docking studies predict that oryzalin binds with an average affinity of 23 nM to a site located beneath the N loop of Toxoplasma -tubulin. This binding site included residues that were mutated in several resistant lines. Moreover, parallel analysis of Bos taurus -tubulin indicated that oryzalin did not interact with this site and had a significantly decreased, nonspecific affinity for vertebrate -tubulin. We propose that the dinitroanilines act through a novel mechanism, by disrupting M-N loop contacts. These compounds also represent the first class of drugs that act on -tubulin function.

Corresponding author and current address: Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697. E-mail address: naomi{at}borcim.wustl.edu.

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