Year: 2026
Type: article
Abstract: , Cif is an epoxide hydrolase that acts as a virulence factor in the context of cystic fibrosis and thus represents a target for therapeutic inhibition. Here, we present the structures of several high-affinity inhibitory nanobodies, each bound to Cif. Comparison reveals two classes of nanobodies with distinct CDR sequences and convergent recognition strategies. Mimicry between CDR3 and CDR2 loops positions an aromatic residue for insertion through the active-site gate, accessing a cryptic epitope, which sterically blocks substrate access and provides an anchor point for high-affinity engagement. Projection of either inhibitory CDR toward the active-site entrance requires a relative 90° rotation of the core immunoglobulin domain, and yet both classes engage the same set of stereochemical handholds within a highly overlapping shared epitope. The structurally distinct paratopes thus represent fundamentally distinct solutions, reflecting the remarkable capacity of the immune system to solve highly constrained molecular recognition challenges.
Source: Journal of Structural Biology X
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,020
Funders: U.S. Department of Energy, Cystic Fibrosis Foundation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Emory University, Dartmouth College, Dartmouth Cancer Center, National Institutes of Health, Office of Science, University of California, Davis, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences, Biological and Environmental Research, Brookhaven National Laboratory
Awards: G1285306620, G1867732070, G2004402655, G241279073, G283689134, G3067052642, G3262563802, G357145406, G3728080647, G4657376766, Mechanism of Cif Virulence: A Bacterial Strategy to Subvert Host-Cell Defenses, G5493493709, G5765906131, G6059574520, G6816383395, G7058390936, G7463374569, G8701900045, Center for Biomolecular Structure (CBMS), Cancer Center Support Grant, Host-Microbe Interactions, The Institute for Biomolecular Targeting, Bioactive lipids as effectors and indicators of the deleterious effects of environmental exposure on chronic diseases, Center for Quantitative Biology: A focus on "omics", from organisms to single cells, DartCF: The Dartmouth Cystic Fibrosis Research Center, G930920969
OpenAlex ID: W7214952562