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Publication Abstract from PubMed

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.

Structure-guided discovery of a single-domain antibody agonist against human apelin receptor.,Ma Y, Ding Y, Song X, Ma X, Li X, Zhang N, Song Y, Sun Y, Shen Y, Zhong W, Hu LA, Ma Y, Zhang MY Sci Adv. 2020 Jan 15;6(3):eaax7379. doi: 10.1126/sciadv.aax7379. eCollection 2020, Jan. PMID:31998837^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.