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

Thomas L. Williams, Grégory Verdon, Rhoda E. Kuc, Heather Currinn, Brian Bender, Nicolae Solcan, Oliver Schlenker, Robyn G. C. Macrae, Jason Brown, Marco Schütz, Andrei Zhukov, Sanjay Sinha, Chris Graaf, Stefan Gräf, Janet J. Maguire, Alastair J. H. Brown () and Anthony P. Davenport ()
Additional contact information
Thomas L. Williams: University of Cambridge
Grégory Verdon: Nxera Pharma UK Limited (Sosei Heptares), Steinmetz Building, Granta Park
Rhoda E. Kuc: University of Cambridge
Heather Currinn: Nxera Pharma UK Limited (Sosei Heptares), Steinmetz Building, Granta Park
Brian Bender: Nxera Pharma UK Limited (Sosei Heptares), Steinmetz Building, Granta Park
Nicolae Solcan: Nxera Pharma UK Limited (Sosei Heptares), Steinmetz Building, Granta Park
Oliver Schlenker: Nxera Pharma UK Limited (Sosei Heptares), Steinmetz Building, Granta Park
Robyn G. C. Macrae: University of Cambridge
Jason Brown: Nxera Pharma UK Limited (Sosei Heptares), Steinmetz Building, Granta Park
Marco Schütz: Nxera Pharma UK Limited (Sosei Heptares), Steinmetz Building, Granta Park
Andrei Zhukov: Nxera Pharma UK Limited (Sosei Heptares), Steinmetz Building, Granta Park
Sanjay Sinha: Jeffrey Cheah Biomedical Centre, University of Cambridge
Chris Graaf: Nxera Pharma UK Limited (Sosei Heptares), Steinmetz Building, Granta Park
Stefan Gräf: Cambridge Biomedical Campus
Janet J. Maguire: University of Cambridge
Alastair J. H. Brown: Nxera Pharma UK Limited (Sosei Heptares), Steinmetz Building, Granta Park
Anthony P. Davenport: University of Cambridge

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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 T892.64 as important in the ELA binding site, and R1684.64 as forming extensive interactions with the C-termini of both peptides. Base editing to introduce an R/H1684.64 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, small molecule agonist, CMF-019, which reveals a deeper binding mode versus the endogenous peptides at lipophilic pockets between transmembrane helices associated with GPCR activation. Overall, the data provide proof-of-principle for using genetic variation to identify key sites regulating receptor-ligand engagement.

Date: 2024
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DOI: 10.1038/s41467-024-55381-w

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