6Z3T

Structure of canine Sec61 inhibited by mycolactone

Summary for 6Z3T

• Entry DOI: 10.2210/pdb6z3t/pdb
• EMDB information: 11064
• Descriptor: Protein transport protein Sec61 subunit alpha isoform 1, Protein transport protein Sec61 subunit gamma, Protein transport protein Sec61 subunit beta, ... (4 entities in total)
• Functional Keywords: sec61; mycolactone; ribosome-translocon complex; translocation inhibitor, membrane protein
• Biological source: Canis lupus familiaris (Dog); More
• Total number of polymer chains: 3
• Total formula weight: 62494.84

Authors

Gerard, S.F.,Higgins, M.K. (deposition date: 2020-05-21, release date: 2020-07-22, Last modification date: 2024-05-22)

Primary citation

Gerard, S.F.,Hall, B.S.,Zaki, A.M.,Corfield, K.A.,Mayerhofer, P.U.,Costa, C.,Whelligan, D.K.,Biggin, P.C.,Simmonds, R.E.,Higgins, M.K.
Structure of the Inhibited State of the Sec Translocon.
Mol.Cell, 79:406-415.e7, 2020

PubMed 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.

PubMed: 32692975
DOI: 10.1016/j.molcel.2020.06.013

Experimental method

ELECTRON MICROSCOPY (2.69 Å)