8TH3

Structure of AT118-H Nanobody Antagonist in Complex with the Angiotensin II Type I Receptor

Summary for 8TH3

• Entry DOI: 10.2210/pdb8th3/pdb
• EMDB information: 41248 41249
• Descriptor: AT118-H nanobody, Type-1 angiotensin II receptor, Soluble cytochrome b562 complex, BAG2 Anti-BRIL Fab Heavy Chain, BAG2 Anti-BRIL Fab Light Chain, ... (4 entities in total)
• Functional Keywords: g protein-coupled receptor, nanobody, signaling protein-immune system complex, signaling protein/immune system
• Biological source: Camelidae; More
• Total number of polymer chains: 4
• Total formula weight: 179783.30

Authors

Skiba, M.A.,Kruse, A.C. (deposition date: 2023-07-13, release date: 2024-05-22, Last modification date: 2024-12-04)

Primary citation

Skiba, M.A.,Sterling, S.M.,Rawson, S.,Zhang, S.,Xu, H.,Jiang, H.,Nemeth, G.R.,Gilman, M.S.A.,Hurley, J.D.,Shen, P.,Staus, D.P.,Kim, J.,McMahon, C.,Lehtinen, M.K.,Rockman, H.A.,Barth, P.,Wingler, L.M.,Kruse, A.C.
Antibodies expand the scope of angiotensin receptor pharmacology.
Nat.Chem.Biol., 20:1577-1585, 2024

PubMed Abstract: G-protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small-molecule research compounds and therapeutic drugs. While most of these ligands bind to their target GPCR with high affinity, selectivity is often limited at the receptor, tissue and cellular levels. Antibodies have the potential to address these limitations but their properties as GPCR ligands remain poorly characterized. Here, using protein engineering, pharmacological assays and structural studies, we develop maternally selective heavy-chain-only antibody ('nanobody') antagonists against the angiotensin II type I receptor and uncover the unusual molecular basis of their receptor antagonism. We further show that our nanobodies can simultaneously bind to angiotensin II type I receptor with specific small-molecule antagonists and demonstrate that ligand selectivity can be readily tuned. Our work illustrates that antibody fragments can exhibit rich and evolvable pharmacology, attesting to their potential as next-generation GPCR modulators.

PubMed: 38744986
DOI: 10.1038/s41589-024-01620-6

Experimental method

ELECTRON MICROSCOPY (3 Å)