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Druggable allosteric sites in β-propeller lectins

MPG-Autoren
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Shanina,  Elena
Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

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Seeberger,  Peter H.
Peter H. Seeberger - Automated Systems, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

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Rademacher,  Christoph
Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

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Zitation

Shanina, E., Kuhaudomlarp, S., Lal, K., Seeberger, P. H., Imberty, A., & Rademacher, C. (2022). Druggable allosteric sites in β-propeller lectins. Angewandte Chemie International Edition, 61(1): e202109339. doi:10.1002/anie.202109339.


Zitierlink: https://hdl.handle.net/21.11116/0000-0009-6D1A-1
Zusammenfassung
Carbohydrate-binding proteins (lectins) are auspicious targets in drug discovery to combat antimicrobial resistance; however, its non-carbohydrate drug-like inhibitors are still spacious. Here, we present a druggable pocket in a β-propeller lectin BambL from  Burkholderia ambifaria  as a potential target for allosteric inhibitors. This site was identified employing  19 F NMR fragment screening and a computational pocket prediction algorithm SiteMap. The structure-activity relationship study revealed the most promising fragment with a dissociation constant of 0.3±0.1 mM and a ligand efficiency of 0.3 kcal mol-1 HA-1 that affected the orthosteric site. This effect was substantiated by site-directed mutagenesis in the orthosteric and secondary pockets. Future drug-discovery campaigns that aim to develop small molecule inhibitors can benefit from allosteric sites in lectins as a new therapeutic approach against antibiotic-resistant pathogens.