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Crystal structure of the Galectin-3 complex with FN3con-7, an mRNA display-derived binding protein
Structural highlights
FunctionLEG3_HUMAN Galactose-specific lectin which binds IgE. May mediate with the alpha-3, beta-1 integrin the stimulation by CSPG4 of endothelial cells migration. Together with DMBT1, required for terminal differentiation of columnar epithelial cells during early embryogenesis (By similarity). In the nucleus: acts as a pre-mRNA splicing factor. Involved in acute inflammatory responses including neutrophil activation and adhesion, chemoattraction of monocytes macrophages, opsonization of apoptotic neutrophils, and activation of mast cells.[1] [2] [3] Publication Abstract from PubMedProtein biosensors are important tools in research, bioengineering, and diagnostics. Unlike fully integrated single-component biosensors, two-component biosensors are modular and can be rapidly adapted to new targets by replacing binding elements. However, their utility is limited by a "hook effect," where high analyte concentrations lead to dissociation of the signalling complex and signal loss. We address this challenge by utilizing sequential mRNA display selection campaigns to develop high-affinity, cooperative FN3con (monobody) binding domains to Galectin-3, a protein biomarker of heart failure. Two-component biosensors equipped with such cooperative binders were devoid of the hook effect and demonstrated 5-fold higher sensitivity to Galectin-3 compared to systems based on non-cooperative binding domains. High-resolution crystal structures of cooperative and non-cooperative binding domains revealed how interactions between the two domains establish a cooperative Galectin-3 binding interface. The results and experimental approaches presented in this work enable the construction of high-performance biosensors for diverse applications. Cooperative Binding Domains Enhance Sensitivity and Overcome the Hook Effect in Two-Component Protein Biosensors.,Mutschler R, Caputo AT, Guo Z, Fiorito MM, Hayat IF, Newton S, Zhang X, Karunathilaka N, Duval C, Brazel H, Chan W, Kostner K, Korczyk D, Abankwa DK, Atherton JJ, Coats AJS, Punyadeera C, Alexandrov K, Cui Z ACS Sens. 2026 Mar 27;11(3):2870-2879. doi: 10.1021/acssensors.6c00488. Epub 2026 , Mar 9. PMID:41801969[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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