A Cryptic Pocket Allosterically Modulates Oligosaccharide Binding to DC-SIGN
DC-SIGN is a C-type lectin receptor expressed on antigen-presenting cells that is 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 the oligosaccharide affinity via the extended carbohydrate binding site. While Ca<sup>2+</sup> coordination at the canonical binding site remains unaffected, our data reveal a complex interplay between the Ca<sup>2+</sup> 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.
Authors
- Carlos P. Modenutti (ORCID: https://orcid.org/0000-0001-5352-7234)
- Jan-Oliver Kapp-Joswig (ORCID: https://orcid.org/0000-0003-1492-3757)
- Jonathan Lefèbre (ORCID: https://orcid.org/0000-0001-8505-2181)
- Stevan Aleksić (ORCID: https://orcid.org/0000-0002-3891-7151)
- Annika Balke (ORCID: https://orcid.org/0000-0001-8469-6911)
- Patrick Scheerer (ORCID: https://orcid.org/0000-0001-5028-2075)
- Elena Georgieva (ORCID: https://orcid.org/0000-0002-5844-6182)
- Bettina G. Keller (ORCID: https://orcid.org/0000-0002-7051-0888)
- Marcelo Daniel Gamarra (ORCID: https://orcid.org/0009-0008-6562-3619)
- Christoph Rademacher
- Maurice Besch (ORCID: https://orcid.org/0000-0001-9242-0261)
- Henry Flatau
- Gregor Suchy
Institutions
- University of Vienna (AT)
- Universidad de Flores (AR)
- Max Perutz Labs (AT)
- Humboldt-Universität zu Berlin (DE)
- Istituto di Biologia e Biotecnologia Agraria (IT)
- Toxicologie, Pharmacologie et Signalisation Cellulaire (FR)
- Fundación Ciencias Exactas y Naturales (AR)
- Freie Universität Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- JACS Au
- Published
- 2026-01-20
- DOI
- https://doi.org/10.1021/jacsau.5c01465
- Primary Topic
- Glycosylation and Glycoproteins Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00