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Pironetin Binds Covalently to αCys316 and Perturbs a Major Loop and Helix of α-Tubulin to Inhibit Microtubule Formation.
Journal article

Pironetin Binds Covalently to αCys316 and Perturbs a Major Loop and Helix of α-Tubulin to Inhibit Microtubule Formation.

  • Prota AE Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland. Electronic address: andrea.prota@psi.ch.
  • Setter J Department of Protein Sciences, Seattle Genetics, Inc., Bothell, WA 98021, USA.
  • Waight AB Department of Protein Sciences, Seattle Genetics, Inc., Bothell, WA 98021, USA.
  • Bargsten K Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland.
  • Murga J Depart. de Q. Inorgánica y Orgánica, Univ. Jaume I, 12071 Castellón, Spain.
  • Diaz JF Chemical and Physical Biology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas CIB-CSIC, 28040 Madrid, Spain.
  • Steinmetz MO Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland. Electronic address: michel.steinmetz@psi.ch.
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  • 2016-07-11
Published in:
  • Journal of molecular biology. - 2016
X-ray crystallography
anticancer drug
microtubule-targeting agents
molecular mechanism of action
protein–ligand interactions
Animals
Antineoplastic Agents
Binding Sites
Biological Products
Cattle
Microtubules
Protein Structural Elements
Pyrones
Sheep
Tubulin
English Microtubule-targeting agents are among the most powerful drugs used in chemotherapy to treat cancer patients. Pironetin is a natural product that displays promising anticancer properties by binding to and potently inhibiting tubulin assembly into microtubules; however, its molecular mechanism of action remained obscure. Here, we solved the crystal structure of the tubulin-pironetin complex and found that the compound covalently binds to Cys316 of α-tubulin. The structure further revealed that pironetin perturbs the T7 loop and helix H8 of α-tubulin. Since both these elements are essential for establishing longitudinal tubulin contacts in microtubules, this result explains how pironetin inhibits the formation of microtubules. Together, our data define the molecular details of the pironetin binding site on α-tubulin and thus offer a promising basis for the rational design of pironetin variants with improved activity profiles. They further extend our knowledge on strategies evolved by natural products to target and perturb the microtubule cytoskeleton.
Language
  • English
Open access status
green
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Persistent URL
https://sonar.ch/global/documents/853
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