Year: 2026
Type: article
Abstract: DC-SIGN is a C-type lectin receptor expressed on antigen-presenting cells, crucial for pathogen recognition and immune modulation. Here, we identify and characterize a previously unrecognized cryptic allosteric pocket in DC-SIGN using molecular dynamics simulations, NMR spectroscopy, cryogenic electron microscopy and biochemical assays. Rotation of the gatekeeper residue M270 exposes the pocket whose occupancy modulates glycan binding. Mutations M270F and T314A mimic the occupied and unoccupied states of this pocket, respectively, shifting the conformational equilibrium of α-helix 2 and altering oligosaccharide affinity via the extended carbohydrate binding site. While Ca²⁺ coordination at the canonical binding site remains unaffected, our data reveal a complex interplay between the Ca²⁺ binding sites and the canonical and extended glycan binding surfaces. These findings uncover a hierarchical allosteric mechanism that enables selective tuning of glycan affinity and suggest the cryptic pocket as a novel target for drug discovery in C-type lectins.
Source: JACS Au
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,500
Funders: European Commission, Deutscher Akademischer Austauschdienst, Deutsche Forschungsgemeinschaft, Fonds National de la Recherche Luxembourg, Consejo Nacional de Investigaciones Científicas y Técnicas, Universität Wien, Universidad de Buenos Aires, Humboldt-Universität zu Berlin, Freie Universität Berlin, H2020 Marie Skłodowska-Curie Actions
Awards: Allostery in Drug Discovery, EXC 2008: Unifying Systems in Catalysis "UniSysCat", G3390287098, G4075482350, G434337789, SFB 1423: Strukturelle Dynamik der GPCRAktivierung und Signaltransduktion, G5022471123, G5896580117, G6029886166, GRK 2662: "Charging into the future”: Verständnis der Wechselwirkung von Polyelektrolyten mit Biosystemen, G7408414608, SFB 1078: Proteinfunktion durch Protonierungsdynamik, Allostery in Drug Discovery, G8616241190
OpenAlex ID: W7124921080