ForceÀdistance measurements have provided a means of looking at interactions of the intact extracellular domain of DC-SIGN with ligands. 18 In these experiments, an N-terminal histidine tag was used to anchor the protein and project the extracellular domain of DC-SIGN from the surface of one membrane, which was apposed to a second membrane bearing a neoglycolipid with a high-mannose oligosaccharide headgroup ( Figure 1C ). Measurement of the distance dependence of the interaction force between the membranes demonstrated that DC-SIGN undergoes a conformational change driven by engagement with ligand. This change reflects flexibility in the linkage between the neck and the CRD.