Abstract
A critical step in infections is the attachment of many microorganisms to host cells using lectins that bind surface glycans, making lectins promising antimicrobial targets. Upon binding mannosylated glycans, FimH, the most studied lectin adhesin of type 1 fimbriae in E. coli, undergoes an allosteric transition from an inactive to an active conformation that can act as a catch-bond. Monoclonal antibodies that alter FimH glycan binding in various ways are available, but the mechanisms of these antibodies remain unclear. Here, we use cryoEM, mass spectrometry, binding assays, and molecular dynamics simulations to determine the structure-function relationships underlying antibody-FimH binding. Our study reveals four distinct antibody mechanisms of action: ligand mimicry by an N-linked, high-mannose glycan; stabilization of the ligand pocket in the inactive state; conformational trapping of the active and inactive states; and locking of the ligand pocket through long-range allosteric effects. These structures reveal multiple mechanisms of antibody responses to an allosteric protein and provide blueprints for new antimicrobial that target adhesins.
Competing Interest Statement
EVS and VT hold US10722580B2 patent "Compositions and methods for treatment and prevention of uropathogenic E. coli infection" that include therapeutic use of mAb475 and mAb926. N.M.R. receives support from Thermo Fisher Scientific under a nondisclosure agreement and is a consultant for Tegmine Therapeutics, Cartography Biosciences, and Augment Biologics.
Footnotes
There were errors in the author list. Evgeni Sokurenko's name was not capitalized, so I fixed that. And I changed the corresponding author to me (Justin Kollman) - the three last authors are co-corresponding, but it seems I can only select one author for this, and I will handle the manuscript and updates. Otherwise, the rest of the manuscript is untouched.
