Modifying a Hydroxyl Patch in Glucagon-like Peptide 1 Produces Biased Agonists with Unique Signaling Profiles.
Basic Information
ID: ALA5126621
Journal: J Med Chem
Title: Modifying a Hydroxyl Patch in Glucagon-like Peptide 1 Produces Biased Agonists with Unique Signaling Profiles.
Authors: Wang P, Hill TA, Mitchell J, Fitzsimmons RL, Xu W, Loh Z, Suen JY, Lim J, Iyer A, Fairlie DP.
Abstract: Glucagon-like peptide-1 (GLP-1) lowers blood glucose by inducing insulin but also has other poorly understood properties. Here, we show that hydroxy amino acids (Thr11, Ser14, Ser17, Ser18) in GLP-1(7-36) act in concert to direct cell signaling. Mutating any single residue to alanine removes one hydroxyl group, thereby reducing receptor affinity and cAMP 10-fold, with Ala11 or Ala14 also reducing β-arrestin-2 10-fold, while Ala17 or Ala18 also increases ERK1/2 phosphorylation 5-fold. Multiple alanine mutations more profoundly bias signaling, differentially silencing or restoring one or more signaling properties. Mutating three serines silences only ERK1/2, the first example of such bias. Mutating all four residues silences β-arrestin-2, ERK1/2, and Ca2+ maintains the ligand and receptor at the membrane but still potently stimulates cAMP and insulin secretion in cells and mice. These novel findings indicate that hydrogen bonding cooperatively controls cell signaling and highlight an important regulatory hydroxyl patch in hormones that activate class B G protein-coupled receptors.
CiteXplore: 35984914
DOI: 10.1021/acs.jmedchem.2c00653
Patent ID: ┄