Antibodies disrupt bacterial adhesion by ligand mimicry and allosteric interference

Kelli L. Hvorecny, Gianluca Interlandi, Tim S. Veth, Pavel Aprikian, Anna Manchenko, Veronika L. Tchesnokova, Miles S. Dickinson, Joel D. Quispe, Nicholas M. Riley, Rachel E. Klevit, Pearl Magala (), Evgeni V. Sokurenko () and Justin M. Kollman ()
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Kelli L. Hvorecny: University of Washington, Department of Biochemistry
Gianluca Interlandi: University of Washington, Department of Bioengineering
Tim S. Veth: University of Washington, Department of Chemistry
Pavel Aprikian: University of Washington, Department of Microbiology
Anna Manchenko: University of Washington, Department of Microbiology
Veronika L. Tchesnokova: University of Washington, Department of Microbiology
Miles S. Dickinson: University of Washington, Department of Biochemistry
Joel D. Quispe: University of Washington, Department of Biochemistry
Nicholas M. Riley: University of Washington, Department of Chemistry
Rachel E. Klevit: University of Washington, Department of Biochemistry
Pearl Magala: University of Washington, Department of Biochemistry
Evgeni V. Sokurenko: University of Washington, Department of Microbiology
Justin M. Kollman: University of Washington, Department of Biochemistry

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract A critical step in infections is the attachment of microorganisms to host cells using lectins that bind glycans, making lectins promising antimicrobial targets. Upon binding mannosylated glycans, FimH, an adhesin in E. coli, undergoes an allosteric transition from an inactive to an active conformation that can act as a catch-bond. Distinct monoclonal antibodies that alter FimH glycan binding are available, but the mechanisms of action remain unclear. Here, we use cryo-electron microscopy, mass spectrometry, adhesion assays, and molecular dynamics simulations to determine the structure-function relationships underlying antibody-FimH binding. Our study demonstrates four 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 antimicrobials that target adhesins.

Date: 2025
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DOI: 10.1038/s41467-025-65666-3

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