We recently discovered that ternatin-4, a cyclic peptide related to the natural product ternatin, blocks cancer cell proliferation by targeting elongation factor 1A (EF1A). Similar to the unrelated cyclic depsipeptide, didemnin B, ternatin-4 traps EF1A at the ribosome A site, inhibiting translation elongation. Cryo-electron microscopy studies revealed that, while ternatin-4 and didemnin both bind to an interdomain allosteric site on EF1A, the conformation of the EF1A GTPase domain is distinct in the two complexes. In cells, ternatin-4 potently and directly induces proteasome-dependent degradation of EF1A, whereas didemnin does not. We speculate that ternatin-4 induces the accumulation of stalled elongating EF1A/ribosome complexes, which are subsequently recognized and ubiquitinated by an as yet unknown quality control system.

Cyclic peptide ternatin-4 promotes degradation of the translation elongation factor, EF1A

2019 Fall National Meeting

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