Structurally Based Design of Glucagon Mutants That Inhibit Fibril Formation.

ABSTRACT: The peptide hormone glucagon is prescribed as a pharmaceutical compound to treat diabetic hypoglycemia. However, at the acidic pH where it is highly soluble, glucagon rapidly aggregates into inactive and cytotoxic amyloid fibrils. The recently determined high-resolution structure of these fibrils revealed various stabilizing molecular interactions. On the basis of this structure, we have now designed four arginine mutants of glucagon that resist fibrillization at pharmaceutical concentrations for weeks. An S2R, T29R double mutant and a T29R single mutant remove a hydrogen-bonding interaction in the wild-type fibril, whereas a Y13R, A19R double mutant and a Y13R mutant remove a cation-π interaction. ¹H solution nuclear magnetic resonance spectra and ultraviolet absorbance data in

SUBMITTER: Gelenter MD 

PROVIDER: S-EPMC8254510 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature