9EAH

Structure of nanobody AT209 in complex with the olmesartan-bound angiotensin II type I receptor (AT1R)

Summary for 9EAH

• Entry DOI: 10.2210/pdb9eah/pdb
• EMDB information: 47831
• Descriptor: Nanobody AT209,Type-1 angiotensin II receptor,Soluble cytochrome b562, BAG2 Anti-BRIL Fab Heavy Chain, BAG2 Anti-BRIL Fab Light Chain, ... (5 entities in total)
• Functional Keywords: gpcr, at1r, nanobody, membrane protein
• Biological source: Camelidae; More
• Total number of polymer chains: 4
• Total formula weight: 179276.53

Authors

Skiba, M.A.,Kruse, A.C. (deposition date: 2024-11-11, release date: 2025-03-05, Last modification date: 2025-03-26)

Primary citation

Skiba, M.A.,Canavan, C.,Nemeth, G.R.,Liu, J.,Kanso, A.,Kruse, A.C.
Epitope-directed selection of GPCR nanobody ligands with evolvable function.
Proc.Natl.Acad.Sci.USA, 122:e2423931122-e2423931122, 2025

PubMed Abstract: Antibodies have the potential to target G protein-coupled receptors (GPCRs) with high receptor, cellular, and tissue selectivity; however, few antibody ligands for GPCRs exist. Here, we describe a generalizable selection method to enrich for GPCR ligands from a synthetic camelid antibody fragment (nanobody) library. Our strategy yielded multiple nanobody ligands for the angiotensin II type I receptor (AT1R), a prototypical GPCR and important drug target. We found that nanobodies readily act as allosteric modulators, encoding selectivity for both the receptor and chemical features of GPCR ligands. We then used structure-guided design to convert two nanobodies from allosteric ligands to competitive AT1R inhibitors through simple mutations. This work demonstrates that nanobodies can encode multiple pharmacological behaviors and have great potential as evolvable scaffolds for the development of next-generation GPCR therapeutics.

PubMed: 40067891
DOI: 10.1073/pnas.2423931122

Experimental method

ELECTRON MICROSCOPY (3.1 Å)