Premium
Functional association of the N‐terminal residues with the central region in glucagon‐related peptides
Author(s) -
Patterson James T.,
Day Jonathan W.,
Gelfanov Vasily M.,
DiMarchi Richard D.
Publication year - 2011
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.1385
Subject(s) - peptide , incretin , amino acid , agonist , biochemistry , chemistry , glucagon like peptide 1 , peptide sequence , glucagon like peptide 1 receptor , receptor , potency , context (archaeology) , stereochemistry , biology , endocrinology , in vitro , paleontology , gene , type 2 diabetes , diabetes mellitus
GLP‐1 is an incretin peptide involved in the regulation of glucose metabolism and the glucose‐dependent stimulation of insulin secretion. Ex‐4 is a paralog of GLP‐1 that has comparable GLP‐1R potency but extended physiological action. GLP‐1 and Ex‐4 are helical peptides that share ∼50% sequence homology but differ at several residues, notably the second amino acid which controls susceptibility to DPP‐IV cleavage. This single amino acid difference yields divergent receptor potency when studied in the context of the two hormone sequences. Ex‐4 uniquely tolerates Gly2 through select amino acid differences in the middle region of the peptide that are absent in GLP‐1. We report that substitution of Ex‐4 amino acids Glu16, Leu21, and Glu24 to the GLP‐1 sequence enabled Gly2 tolerance. The coordination of the N‐terminus with these central residues shows an interaction of substantial importance not only to DPP‐IV stability but also to receptor activation. Extension of this observation to glucagon‐based co‐agonist peptides showed different structural requirements for effective communication between the N‐terminus and the mid‐section of these peptides in achieving high potency agonism at the GLP‐1 and GCGRs. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.