Structural and functional determination of peptide versus small molecule ligand binding at the apelin receptor.

ABSTRACT: We describe a structural and functional study of the G protein-coupled apelin receptor, which binds two endogenous peptide ligands, apelin and Elabela/Toddler (ELA), to regulate cardiovascular development and function. Characterisation of naturally occurring apelin receptor variants from the UK Genomics England 100,000 Genomes Project, and AlphaFold2 modelling, identifies T89^2.64 as important in the ELA binding site, and R168^4.64 as forming extensive interactions with the C-termini of both peptides. Base editing to introduce an R/H168^4.64 variant into human stem cell-derived cardiomyocytes demonstrates that this residue is critical for receptor binding and function. Additionally, we present an apelin receptor crystal structure bound to the G protein-biased,

SUBMITTER: Williams TL 

PROVIDER: S-EPMC11680790 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature