EMD-11064
Structure of canine Sec61 inhibited by mycolactone
EMD-11064
Single-particle2.69 Å
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Map released: 22/07/2020
Last modified: 22/05/2024
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
Sample: Ribosome-translocon complexes from canine ER microsomes, bound to mycolactone
Fitted models: 6z3t (Avg. Q-score: 0.341)
Deposition Authors: Gerard SF
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Structure of the Inhibited State of the Sec Translocon.
Gerard SF
,
Hall BS
,
Zaki AM
,
Corfield KA,
Mayerhofer PU,
Costa C
,
Whelligan DK
,
Biggin PC
,
Simmonds RE
,
Higgins MK
(2020) Mol Cell , 79 , 406 - 415.e7
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(2020) Mol Cell , 79 , 406 - 415.e7
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.
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.