Signal peptide mimicry primes Sec61 for client-selective inhibition

Rehan, S.; Tranter, D.; Sharp, P. P.; Lowe, E.; Anderl, J.; Muchamuel, T.; Abrishami, V.; Kuivanen, S.; Wenzell, N.; Jennings, A.; Kalyanaraman, C.; Craven, G. B.; Strandin, T.; Javanainen, M.; Vapalahti, O.; Jacobson, M.; McMinn, D.; Kirk, C. J.; Huiskonen, J. T.; Taunton, J.; Paavilainen, V.

doi:10.1101/2022.07.03.498529

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bioRxiv · 10.1101/2022.07.03.498529

Signal peptide mimicry primes Sec61 for client-selective inhibition

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Abstract

Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been hampered by excessive toxicity. Here, we describe KZR-8445, a cyclic depsipeptide that targets the Sec61 translocon and selectively disrupts secretory and membrane protein biogenesis in a signal peptide-dependent manner. KZR-8445 potently inhibits the secretion of proinflammatory cytokines in primary immune cells and is highly efficacious in a mouse model of rheumatoid arthritis. A cryo-EM structure reveals that KZR-8445 occupies the fully opened Se61 lateral gate and blocks access to the lumenal plug domain. KZR-8445 binding stabilizes the lateral gate helices in a manner that traps select signal peptides in the Sec61 channel and prevents their movement into the lipid bilayer. Our results establish a framework for the structure-guided discovery of novel therapeutics that selectively modulate Sec61-mediated protein biogenesis.

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Rehan, S., Tranter, D., Sharp, P. P., Lowe, E., Anderl, J., Muchamuel, T., Abrishami, V., Kuivanen, S., Wenzell, N., Jennings, A., Kalyanaraman, C., Craven, G. B., Strandin, T., Javanainen, M., Vapalahti, O., Jacobson, M., McMinn, D., Kirk, C. J., Huiskonen, J. T., Taunton, J., Paavilainen, V.. 2022-07-05. Signal peptide mimicry primes Sec61 for client-selective inhibition. https://doi.org/10.1101/2022.07.03.498529

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