Biosynthesis of lanthionine-constrained agonists of G protein-coupled receptors.

Biosynthesis of lanthionine-constrained agonists of G protein-coupled receptors.
Biochem Soc Trans. 2020 Oct 30;48(5):2195-2203
Authors: Moll GN, Kuipers A, Rink R, Bosma T, de Vries L, Namsolleck P
Abstract
The conformation with which natural agonistic peptides interact with G protein-coupled receptor(s) (GPCR(s)) partly results from intramolecular interactions such as hydrogen bridges or is induced by ligand-receptor interactions. The conformational freedom of a peptide can be constrained by intramolecular cross-links. Conformational constraints enhance the receptor specificity, may lead to biased activity and confer proteolytic resistance to peptidic GPCR agonists. Chemical synthesis allows to introduce a variety of cross-links into a peptide and is suitable for bulk production of relatively simple lead peptides. Lanthionines are thioether bridged alanines of which the two alanines can be introduced at different distances in chosen positions in a peptide. Thioether bridges are much more stable than disulfide bridges. Biosynthesis of lanthionine-constrained peptides exploiting engineered Gram-positive or Gram-negative bacteria that contain lanthionine-introducing enzymes constitutes a convenient method for discovery of lanthionine-stabilized GPCR agonists. The presence of an N-terminal leader peptide enables dehydratases to dehydrate serines and threonines in the peptide of interest after which a cyclase can couple the formed dehyd...

Source: Biochemical Society Transactions - October 30, 2020 Category: Biochemistry Authors: Moll GN, Kuipers A, Rink R, Bosma T, de Vries L, Namsolleck P Tags: Biochem Soc Trans Source Type: research