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Dinitroaniline Interactions with Tubulin: Genetic and Computational Approaches to Define the Mechanisms of Action and Resistance

  • Naomi Morrissette
  • David Sept
Conference paper
Part of the NATO Science for Peace and Security Series C: Environmental Security book series (NAPSC)

The dinitroanilines are small molecules that selectively bind to plant and protozoan tubulin dimers and disrupt microtubules in these organisms. Despite the high degree of sequence conservation among all tubulins, these compounds do not bind to tubulins from fungi or vertebrates, nor are microtubules in these organisms disrupted by dinitroaniline treatment. Studies on tubulin affinity for dinitroanilines, dinitroaniline effects on microtubule dynamics and the genetics of dinitroaniline resistance in the unicellular alga Chlamydomonas reinhardtii and in the higher plants Eleusine indica and Setaria viridis are summarized here. We also describe our ongoing research which exploits computational methods and the genetics of resistance in the protozoan parasite Toxoplasma gondii to describe the action of the dinitroanilines on tubulin. We conclude that the dinitroanilines bind beneath the H1-S2 (N) loop of α-tubulin and cause this loop to be drawn inwards, disrupting protofilament interactions within the microtubule. Toxoplasma mutations that confer resistance to these compounds appear to act by increasing microtubule stability or by decreasing affinity for dinitro-anilines. Moreover, resistance mutations impose a fitness cost on Toxoplasma, and growth of resistant parasites in the absence of dinitroanilines leads to the spontaneous appearance of suppressor mutations. Many of these secondary mutations are point mutations located in the α- or β-tubulin genes. The suppressor mutations act to improve the growth of Toxoplasma and to decrease resistance to dinitroanilines, indicating that there is a trade-off between dinitroaniline resistance and tubulin function.

Keywords

Docking fitness herbicide microtubule molecular dynamics mutant parasite protozoa resistance Toxoplasma 

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Copyright information

© Springer Science + Business Media B.V. 2008

Authors and Affiliations

  • Naomi Morrissette
    • 1
  • David Sept
    • 2
  1. 1.Department of Molecular Biology and BiochemistryUniversity of California, IrvineIrvineUSA
  2. 2.Department of Biomedical Engineering and the Center for Computational BiologyWashington UniversitySt. LouisUSA

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