EMD-11064

Single-particle
2.69 Å
EMD-11064 Deposition: 21/05/2020
Map released: 22/07/2020
Last modified: 22/05/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-11064

Structure of canine Sec61 inhibited by mycolactone

EMD-11064

Single-particle
2.69 Å
EMD-11064 Deposition: 21/05/2020
Map released: 22/07/2020
Last modified: 22/05/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Canis lupus familiaris
Sample: Ribosome-translocon complexes from canine ER microsomes, bound to mycolactone
Fitted models: 6z3t (Avg. Q-score: 0.341)

Deposition Authors: Gerard SF , Higgins MK
Structure of the Inhibited State of the Sec Translocon.
PUBMED: 32692975
DOI: doi:10.1016/j.molcel.2020.06.013
ISSN: 1097-2765
ASTM: MOCEFL
Abstract:
Protein secretion in eukaryotes and prokaryotes involves a universally conserved protein translocation channel formed by the Sec61 complex. Unrelated small-molecule natural products and synthetic compounds inhibit Sec61 with differential effects for different substrates or for Sec61 from different organisms, making this a promising target for therapeutic intervention. To understand the mode of inhibition and provide insight into the molecular mechanism of this dynamic translocon, we determined the structure of mammalian Sec61 inhibited by the Mycobacterium ulcerans exotoxin mycolactone via electron cryo-microscopy. Unexpectedly, the conformation of inhibited Sec61 is optimal for substrate engagement, with mycolactone wedging open the cytosolic side of the lateral gate. The inability of mycolactone-inhibited Sec61 to effectively transport substrate proteins implies that signal peptides and transmembrane domains pass through the site occupied by mycolactone. This provides a foundation for understanding the molecular mechanism of Sec61 inhibitors and reveals novel features of translocon function and dynamics.