Open AccessIdentification of the Allosteric Binding Site for Thiazolopyrimidine on the C-Type Lectin Langerin
Author(s) -
Hengxi Zhang,
Carlos P. Modenutti,
Yelha Phani Kumar Nekkanti,
Maxime Denis,
Iris A. Bermejo,
Jonathan Lefèbre,
Kateryna Che,
Dong-Yoon Kim,
Marten Kagelmacher,
Dennis Kurzbach,
Marc Nazaré,
Christoph Rademacher
Publication year - 2022
Publication title -
acs chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.899
H-Index - 111
eISSN - 1554-8937
pISSN - 1554-8929
DOI - 10.1021/acschembio.2c00626
Subject(s) - langerin , allosteric regulation , c type lectin , binding site , lectin , biology , innate immune system , mannan binding lectin , computational biology , chemistry , microbiology and biotechnology , biochemistry , receptor , immune system , genetics , dendritic cell
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.