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TitleStructure of the Inhibited State of the Sec Translocon.
Journal, issue, pagesMol Cell, Vol. 79, Issue 3, Page 406-415.e7, Year 2020
Publish dateAug 6, 2020
AuthorsSamuel F Gérard / Belinda S Hall / Afroditi M Zaki / Katherine A Corfield / Peter U Mayerhofer / Catia Costa / Daniel K Whelligan / Philip C Biggin / Rachel E Simmonds / Matthew K Higgins /
PubMed AbstractProtein secretion in eukaryotes and prokaryotes involves a universally conserved protein translocation channel formed by the Sec61 complex. Unrelated small-molecule natural products and synthetic ...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.
External linksMol Cell / PubMed:32692975 / PubMed Central
MethodsEM (single particle)
Resolution2.69 Å
Structure data

11064

6z3t

EMDB-11064, PDB-6z3t:
Structure of canine Sec61 inhibited by mycolactone
Method: EM (single particle) / Resolution: 2.69 Å

Chemicals

ChemComp-Q6B:
[(6~{S},7~{S},9~{Z},12~{R})-12-[(~{Z},2~{S},6~{R},7~{R},9~{R})-4,6-dimethyl-7,9-bis(oxidanyl)dec-4-en-2-yl]-7,9-dimethyl-2-oxidanylidene-1-oxacyclododec-9-en-6-yl] (2~{E},4~{E},6~{E},8~{E},10~{E},12~{S},13~{S},15~{S})-4,6,10-trimethyl-12,13,15-tris(oxidanyl)hexadeca-2,4,6,8,10-pentaenoate

Source
  • canis lupus familiaris (dog)
KeywordsMEMBRANE PROTEIN / Sec61; mycolactone; ribosome-translocon complex; translocation inhibitor

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