# A Cryptic Pocket Allosterically Modulates Oligosaccharide Binding to DC-SIGN

## TL;DR

Researchers discovered a hidden pocket in DC-SIGN that controls how it binds sugars, offering new insights for drug development.

## Contribution

The study reveals a novel cryptic allosteric pocket in DC-SIGN that modulates oligosaccharide binding through conformational changes.

## Key findings

- Rotation of residue M270 exposes a cryptic pocket that modulates glycan binding.
- Mutations M270F and T314A mimic occupied and unoccupied states of the pocket, altering oligosaccharide affinity.
- The cryptic pocket interacts with glycan binding sites and Ca2+ coordination, revealing a hierarchical allosteric mechanism.

## Abstract

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 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.