Chiral mutagenesis of insulin. Foldability and function are inversely regulated by a stereospecific switch in the B chain.

ABSTRACT: How insulin binds to its receptor is unknown despite decades of investigation. Here, we employ chiral mutagenesis-comparison of corresponding d and l amino acid substitutions in the hormone-to define a structural switch between folding-competent and active conformations. Our strategy is motivated by the T --> R transition, an allosteric feature of zinc-hexamer assembly in which an invariant glycine in the B chain changes conformations. In the classical T state, Gly(B8) lies within a beta-turn and exhibits a positive phi angle (like a d amino acid); in the alternative R state, Gly(B8) is part of an alpha-helix and exhibits a negative phi angle (like an l amino acid). Respective B chain libraries containing mixtures of d or l substitutions at B8 exhibit a stereospecific perturbation of insul

SUBMITTER: Nakagawa SH 

PROVIDER: S-EPMC3845378 | biostudies-literature | 2005 Apr

REPOSITORIES: biostudies-literature