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Publication Abstract from PubMed

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 alpha-tubulin. The structure further revealed that pironetin perturbs the T7 loop and helix H8 of alpha-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 alpha-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.

Pironetin Binds Covalently to alphaCys316 and Perturbs a Major Loop and Helix of alpha-Tubulin to Inhibit Microtubule Formation.,Prota AE, Setter J, Waight AB, Bargsten K, Murga J, Diaz JF, Steinmetz MO J Mol Biol. 2016 Jul 6. pii: S0022-2836(16)30245-5. doi:, 10.1016/j.jmb.2016.06.023. PMID:27395016^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.