4yj3 Citations

Structures of potent anticancer compounds bound to tubulin.

Protein Sci 24 1164-72 (2015)
Cited: 11 times
EuropePMC logo PMID: 25970265

Abstract

Small molecules that bind to tubulin exert powerful effects on cell division and apoptosis (programmed cell death). Cell-based high-throughput screening combined with chemo/bioinformatic and biochemical analyses recently revealed a novel compound MI-181 as a potent mitotic inhibitor with heightened activity towards melanomas. MI-181 causes tubulin depolymerization, activates the spindle assembly checkpoint arresting cells in mitosis, and induces apoptotic cell death. C2 is an unrelated compound previously shown to have lethal effects on microtubules in tumorigenic cell lines. We report 2.60 Å and 3.75 Å resolution structures of MI-181 and C2, respectively, bound to a ternary complex of αβ-tubulin, the tubulin-binding protein stathmin, and tubulin tyrosine ligase. In the first of these structures, our crystallographic results reveal a unique binding mode for MI-181 extending unusually deep into the well-studied colchicine-binding site on β-tubulin. In the second structure the C2 compound occupies the colchicine-binding site on β-tubulin with two chemical moieties recapitulating contacts made by colchicine, in combination with another system of atomic contacts. These insights reveal the source of the observed effects of MI-181 and C2 on microtubules, mitosis, and cultured cancer cell lines. The structural details of the interaction between tubulin and the described compounds may guide the development of improved derivative compounds as therapeutic candidates or molecular probes to study cancer cell division.

Reviews - 4yj3 mentioned but not cited (1)

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Reviews citing this publication (3)

  1. Antitubulin sulfonamides: The successful combination of an established drug class and a multifaceted target. Vicente-Blázquez A, González M, Álvarez R, Del Mazo S, Medarde M, Peláez R. Med Res Rev 39 775-830 (2019)
  2. Dissecting the mechanisms of cell division. Ong JY, Torres JZ. J Biol Chem 294 11382-11390 (2019)
  3. Upstream biomanufacturing of pharmaceutical colchicine. Sivakumar G. Crit Rev Biotechnol 38 83-92 (2018)

Articles citing this publication (5)