A common mechanism of Sec61 translocon inhibition by small molecules

Itskanov, Samuel and Wang, Laurie and Junne, Tina and Sherriff, Rumi and Xiao, Li and Blanchard, Nicolas and Shi, Wei Q. and Forsyth, Craig and Hoepfner, Dominic and Spiess, Martin and Park, Eunyong. (2023) A common mechanism of Sec61 translocon inhibition by small molecules. Nature Chemical Biology.

[img] PDF - Accepted Version

Official URL: https://edoc.unibas.ch/94636/

Downloads: Statistics Overview


The Sec61 complex forms a protein-conducting channel in the endoplasmic reticulum membrane that is required for secretion of soluble proteins and production of many membrane proteins. Several natural and synthetic small molecules specifically inhibit Sec61, generating cellular effects that are useful for therapeutic purposes, but their inhibitory mechanisms remain unclear. Here we present near-atomic-resolution structures of human Sec61 inhibited by a comprehensive panel of structurally distinct small molecules-cotransin, decatransin, apratoxin, ipomoeassin, mycolactone, cyclotriazadisulfonamide and eeyarestatin. All inhibitors bind to a common lipid-exposed pocket formed by the partially open lateral gate and plug domain of Sec61. Mutations conferring resistance to the inhibitors are clustered at this binding pocket. The structures indicate that Sec61 inhibitors stabilize the plug domain in a closed state, thereby preventing the protein-translocation pore from opening. Our study provides the atomic details of Sec61-inhibitor interactions and the structural framework for further pharmacological studies and drug design.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Biochemistry (Spiess)
UniBasel Contributors:Spiess, Martin and Junne Bieri, Tina
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Publishing Group
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
edoc DOI:
Last Modified:11 Nov 2023 02:30
Deposited On:19 Sep 2023 12:58

Repository Staff Only: item control page