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MBC in Press, published online ahead of print January 23, 2004
Mol. Biol. Cell 10.1091/mbc.E03-07-0530

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Submitted on July 25, 2003
Revised on January 7, 2004
Accepted on January 7, 2004

Dinitroanilines Bind {alpha}-tubulin to Disrupt Microtubules

Naomi S. Morrissette1*, Arpita Mitra2, David Sept3, and L. David Sibley1

1 Department of Molecular Microbiology, Washington University School of Medicine, St Louis MO 63110
2 Department of Chemical Engineering and Center for Computational Biology, Washington University School of Medicine, St Louis MO 63110
3 Department of Biomedical Engineering and Center for Computational Biology, Washington University School of Medicine, St Louis MO 63110

* Corresponding author. E-mail address: naomi{at}borcim.wustl.edu.

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 forty-nine independent resistant Toxoplasma gondii lines after chemical mutagenesis. All twenty-three of the lines that we examined harbored single point mutations in {alpha}-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 {alpha}-tubulin. Docking studies predict that oryzalin binds with an average affinity of 23 nM to a site located beneath the N loop of Toxoplasma {alpha}-tubulin. This binding site included residues that were mutated in several resistant lines. Moreover, parallel analysis of Bos taurus {alpha}-tubulin indicated that oryzalin did not interact with this site and had a significantly decreased, nonspecific affinity for vertebrate {alpha}-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 {alpha}-tubulin function.




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