biostudies-literatureYussif BMHHS | NIH | National Institute of General Medical SciencesUniversity of Nebraska-LincolnNIGMS NIH HHSe2217604120https://www.ebi.ac.uk/biostudies/studies/S-EPMC10089201biostudies-literatureUnknown120(11)The l- to d-amino acid residue isomerization of neuropeptides is an understudied post-translational modification found in animals across several phyla. Despite its physiological importance, little information is available regarding the impact of endogenous peptide isomerization on receptor recognition and activation. As a result, the full roles peptide isomerization play in biology are not well understood. Here, we identify that the <i>Aplysia</i> allatotropin-related peptide (ATRP) signaling system utilizes l- to d-residue isomerization of one amino acid residue in the neuropeptide ligand to modulate selectivity between two distinct G protein-coupled receptors (GPCRs). We first identified a novel receptor for ATRP that is selective for the D2-ATRP form, which bears a single d-phenylalaninProceedings of the National Academy of Sciences of the United States of AmericaEndogenous l- to d-amino acid residue isomerization modulates selectivity between distinct neuropeptide receptor family members.PMC10089201N/AP20 GM113126Checco JWYussif BMBlasing CVfalseEndogenous l- to d-amino acid residue isomerization modulates selectivity between distinct neuropeptide receptor family members.The l- to d-amino acid residue isomerization of neuropeptides is an understudied post-translational modification found in animals across several phyla. Despite its physiological importance, little information is available regarding the impact of endogenous peptide isomerization on receptor recognition and activation. As a result, the full roles peptide isomerization play in biology are not well understood. Here, we identify that the <i>Aplysia</i> allatotropin-related peptide (ATRP) signaling system utilizes l- to d-residue isomerization of one amino acid residue in the neuropeptide ligand to modulate selectivity between two distinct G protein-coupled receptors (GPCRs). We first identified a novel receptor for ATRP that is selective for the D2-ATRP form, which bears a single d-phenylalanin2023-01-01T00:00:00Z2023 Mar2026-07-14T23:37:49.237Z2025-04-19T04:58:44.968ZS-EPMC100892013687784910.1073/pnas.2217604120