Structure-guided discovery of a single-domain antibody agonist against human apelin receptor

Sci Adv. 2020 Jan 15;6(3):eaax7379. doi: 10.1126/sciadv.aax7379. eCollection 2020 Jan.


Developing antibody agonists targeting the human apelin receptor (APJ) is a promising therapeutic approach for the treatment of chronic heart failure. Here, we report the structure-guided discovery of a single-domain antibody (sdAb) agonist JN241-9, based on the cocrystal structure of APJ with an sdAb antagonist JN241, the first cocrystal structure of a class A G protein-coupled receptor (GPCR) with a functional antibody. As revealed by the structure, JN241 binds to the extracellular side of APJ, makes critical contacts with the second extracellular loop, and inserts the CDR3 into the ligand-binding pocket. We converted JN241 into a full agonist JN241-9 by inserting a tyrosine into the CDR3. Modeling and molecular dynamics simulation shed light on JN241-9-stimulated receptor activation, providing structural insights for finding agonistic antibodies against class A GPCRs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apelin Receptors / agonists*
  • Apelin Receptors / chemistry*
  • Binding Sites
  • Drug Design
  • Drug Discovery / methods*
  • Humans
  • Molecular Conformation
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Protein Binding
  • Quantitative Structure-Activity Relationship*
  • Single-Domain Antibodies / chemistry*
  • Single-Domain Antibodies / pharmacology*


  • APLNR protein, human
  • Apelin Receptors
  • Single-Domain Antibodies