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

Author

Listed:
  • 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
    Jeffrey Cheah Biomedical Centre, 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
    University of Cambridge
    University of Cambridge, Victor Phillip Dahdaleh Heart & Lung Research Institute)

  • 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)

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.

Suggested Citation

  • 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, 2024. "Structural and functional determination of peptide versus small molecule ligand binding at the apelin receptor," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-55381-w
    DOI: 10.1038/s41467-024-55381-w
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    References listed on IDEAS

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