Identification of the Allosteric Binding Site for Thiazolopyrimidine on the C-Type Lectin Langerin

Hengxi Zhang; Carlos Modenutti; Yelha Phani Kumar Nekkanti; Maxime Denis; Iris A. Bermejo; Jonathan Lefèbre; Kateryna Che; Dongyoon Kim; Marten Kagelmacher; Dennis Kurzbach; Marc Nazaré; Christoph Rademacher

doi:10.1021/acschembio.2c00626

Titel

Identification of the Allosteric Binding Site for Thiazolopyrimidine on the C-Type Lectin Langerin

Autor*in

Hengxi Zhang

Department für Pharmazeutische Wissenschaften, Fakultät für Lebenswissenschaften, Universität Wien

Carlos Modenutti

Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1 14424 Potsdam, Germany

Yelha Phani Kumar Nekkanti

Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Roessle-Strasse 10, 13125 Berlin, Germany

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Abstract

Langerin is a mammalian C-type lectin expressed on Langerhans cells in the skin. As an innate immune cell receptor, Langerin is involved in coordinating innate and adaptive immune responses against various incoming threats. We have previously reported a series of thiazolopyrimidines as murine Langerin ligands. Prompted by the observation that its human homologue exhibits different binding specificities for these small molecules, we report here our investigations to define their exact binding site. By using structural comparison and molecular dynamics simulations, we showed that the nonconserved short loops have a high degree of conformational flexibility between the human and murine homologues. Sequence analysis and mutational studies indicated that a pair of residues are essential for the recognition of the thiazolopyrimidines. Taking solvent paramagnetic relaxation enhancement NMR studies together with a series of peptides occupying the same site, we could define the cleft between the short and long loops as the allosteric binding site for these aromatic heterocycles.

Stichwort

Chemical structureLigandsPeptides and proteinsReaction productsScreening assays

Objekt-Typ

journal article

Sprache

Englisch [eng]

Persistent identifier

phaidra.univie.ac.at/o:2039356

DOI

10.1021/acschembio.2c00626

Erschienen in

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