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  Druggable allosteric sites in β-propeller lectins

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.

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 Creators:
Shanina, Elena1, Author              
Kuhaudomlarp, Sakonwan, Author
Lal, Kanhaya, Author
Seeberger, Peter H.2, Author              
Imberty, Anne, Author
Rademacher, Christoph1, Author              
Affiliations:
1Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society, ou_1863300              
2Peter H. Seeberger - Automated Systems, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society, ou_1863306              

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Free keywords: Allostery, Drug Discovery; Anti-infectives; Glycomimetics; NMR
 Abstract: 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.

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Language(s): eng - English
 Dates: 2021-10-292022
 Publication Status: Published in print
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 Table of Contents: -
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Title: Angewandte Chemie International Edition
  Abbreviation : Angew. Chem. Int. Ed.
Source Genre: Journal
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Publ. Info: Weinheim : Wiley-VCH
Pages: - Volume / Issue: 61 (1) Sequence Number: e202109339 Start / End Page: - Identifier: ISSN: 1433-7851

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Title: Angewandte Chemie
  Abbreviation : Angew. Chem.
Source Genre: Journal
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Publ. Info: Weinheim : Wiley-VCH
Pages: - Volume / Issue: 134 (1) Sequence Number: e202109339 Start / End Page: - Identifier: ISSN: 0044-8249