A common mechanism of Sec61 translocon inhibition by small molecules - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Nature Chemical Biology Année : 2023

A common mechanism of Sec61 translocon inhibition by small molecules

Samuel Itskanov
Laurie Wang
Tina Junne
  • Fonction : Auteur
Rumi Sherriff
Li Xiao
  • Fonction : Auteur
Wei Shi
Craig Forsyth
  • Fonction : Auteur
Dominic Hoepfner
Martin Spiess
Eunyong Park

Résumé

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.

Mots clés

Fichier principal
Vignette du fichier
29542_2_merged_1681286536 copie.pdf (1.09 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-04262928 , version 1 (31-10-2023)

Identifiants

Citer

Samuel Itskanov, Laurie Wang, Tina Junne, Rumi Sherriff, Li Xiao, et al.. A common mechanism of Sec61 translocon inhibition by small molecules. Nature Chemical Biology, 2023, 19 (9), pp.1063-1071. ⟨10.1038/s41589-023-01337-y⟩. ⟨hal-04262928⟩
21 Consultations
18 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More