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TitleAntibodies expand the scope of angiotensin receptor pharmacology.
Journal, issue, pagesNat Chem Biol, Year 2024
Publish dateMay 14, 2024
AuthorsMeredith A Skiba / Sarah M Sterling / Shaun Rawson / Shuhao Zhang / Huixin Xu / Haoran Jiang / Genevieve R Nemeth / Morgan S A Gilman / Joseph D Hurley / Pengxiang Shen / Dean P Staus / Jihee Kim / Conor McMahon / Maria K Lehtinen / Howard A Rockman / Patrick Barth / Laura M Wingler / Andrew C Kruse /
PubMed AbstractG-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 ...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.
External linksNat Chem Biol / PubMed:38744986
MethodsEM (single particle)
Resolution3.0 - 3.3 Å
Structure data

EMDB-41248, PDB-8th3:
Structure of AT118-H Nanobody Antagonist in Complex with the Angiotensin II Type I Receptor
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-41249, PDB-8th4:
Structure of AT118-L Nanobody Antagonist in Complex with the Angiotensin II Type I Receptor and Losartan
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-LSN:
[2-butyl-5-chloranyl-3-[[4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol / medication*YM

Source
  • homo sapiens (human)
  • synthetic construct (others)
  • camelidae (mammal)
  • escherichia coli (E. coli)
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / G protein-coupled receptor / nanobody / SIGNALING PROTEIN-IMMUNE SYSTEM complex

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