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oai:repisalud.isciii.es:20.500.12105/99982025-05-27T13:17:21Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19609

00925njm 22002777a 4500 dc Garcia-Ferrer, Irene author Arêde, Pedro author Gómez-Blanco, Josué author Luque, Daniel author Duquerroy, Stephane author Castón, José R author Goulas, Theodoros author Gomis-Rüth, F Xavier author 2015-07-07 The survival of commensal bacteria requires them to evade host peptidases. Gram-negative bacteria from the human gut microbiome encode a relative of the human endopeptidase inhibitor, α2-macroglobulin (α2M). Escherichia coli α2M (ECAM) is a ∼ 180-kDa multidomain membrane-anchored pan-peptidase inhibitor, which is cleaved by host endopeptidases in an accessible bait region. Structural studies by electron microscopy and crystallography reveal that this cleavage causes major structural rearrangement of more than half the 13-domain structure from a native to a compact induced form. It also exposes a reactive thioester bond, which covalently traps the peptidase. Subsequently, peptidase-laden ECAM is shed from the membrane and may dimerize. Trapped peptidases are still active except against very large substrates, so inhibition potentially prevents damage of large cell envelope components, but not host digestion. Mechanistically, these results document a novel monomeric "snap trap." Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8290-5. 10.1073/pnas.1506538112 1091-6490 0027-8424 Proceedings of the National Academy of Sciences of the United States of America 26100869 http://hdl.handle.net/20.500.12105/9998 X-ray crystal structure Conformational rearrangement Cryo-electron microscopy Gut microbiome Protein inhibitor Structural and functional insights into Escherichia coli α2-macroglobulin endopeptidase snap-trap inhibition