Engineering a therapeutic lectin by uncoupling mitogenicity from antiviral activity.
A key effector route of the Sugar Code involves lectins that exert crucial regulatory controls by targeting distinct cellular glycans. We demonstrate that a single amino-acid substitution in a banana lectin, replacing histidine 84 with a threonine, significantly reduces its mitogenicity, while preserving its broad-spectrum antiviral potency. X-ray crystallography, NMR spectroscopy, and glycocluster assays reveal that loss of mitogenicity is strongly correlated with loss of pi-pi stacking between aromatic amino acids H84 and Y83, which removes a wall separating two carbohydrate binding sites, thus diminishing multivalent interactions. On the other hand, monovalent interactions and antiviral activity are preserved by retaining other wild-type conformational features and possibly through unique contacts involving the T84 side chain. Through such fine-tuning, target selection and downstream effects of a lectin can be modulated so as to knock down one activity, while preserving another, thus providing tools for therapeutics and for understanding the Sugar Code.
Swanson, MD; Boudreaux, DM; Salmon, L; Chugh, J; Winter, HC; Meagher, JL; André, S; Murphy, PV; Oscarson, S; Roy, R; King, S; Kaplan, MH; Goldstein, IJ; Tarbet, EB; Hurst, BL; Smee, DF; de la Fuente, C; Hoffmann, H-H; Xue, Y; Rice, CM; Schols, D; Garcia, JV; Stuckey, JA; Gabius, H-J; Al-Hashimi, HM; Markovitz, DM
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