6KNM

Apelin receptor in complex with single domain antibody

Summary for 6KNM

• Entry DOI: 10.2210/pdb6knm/pdb
• Descriptor: Apelin receptor,Rubredoxin,Apelin receptor, Single domain antibody JN241, ZINC ION (3 entities in total)
• Functional Keywords: gpcr, single-domain antibody, antagonist, agonist, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 60275.35

Authors

Ma, Y.B.,Ding, Y.,Song, X.,Ma, X.,Li, X.,Zhang, N.,Song, Y.,Sun, Y.,Shen, Y.,Zhong, W.,Hu, L.A.,Ma, Y.L.,Zhang, M.Y. (deposition date: 2019-08-06, release date: 2020-01-29, Last modification date: 2024-11-13)

Primary citation

Ma, Y.,Ding, Y.,Song, X.,Ma, X.,Li, X.,Zhang, N.,Song, Y.,Sun, Y.,Shen, Y.,Zhong, W.,Hu, L.A.,Ma, Y.,Zhang, M.Y.
Structure-guided discovery of a single-domain antibody agonist against human apelin receptor.
Sci Adv, 6:eaax7379-eaax7379, 2020

PubMed Abstract: 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.

PubMed: 31998837
DOI: 10.1126/sciadv.aax7379

Experimental method

X-RAY DIFFRACTION (3.2 Å)