Topogenic sequence recognition at TIM complexes revealed by a stendomycin-bound structure.

Stendomycin binds the protein translocation cavity of yeast Tim17, mimicking α-helical topogenic sequences and enabling mechanistic overlap with Tim22 insertase function.

• Why it matters: TIM23 and TIM22 share homologous subunits but their topogenic recognition mechanisms are unclear, limiting understanding of how imported proteins are sorted across the mitochondrial inner membrane.
• What they did: Using structural and functional approaches, cryogenic-electron microscopy mapped stendomycin binding to Tim17’s cavity; Tim22 did not bind, but a single cavity-equivalent mutation enabled binding.
• The result: Tim17 and Tim22 cavities are largely interchangeable without disrupting function, and stendomycin collapses membrane potential, likely via Tim17- or Tim22-dependent translocation across the IM.

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