8th3

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

spinqualitylabelsall models 8th3, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8th3 is a 4 chain structure with sequence from Camelidae, Escherichia coli, Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3Å Ligands: Y01 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease AGTR1_HUMAN NON RARE IN EUROPE: Essential hypertension;Renal tubular dysgenesis of genetic origin. The disease is caused by mutations affecting the gene represented in this entry. Function C562_ECOLX Electron-transport protein of unknown function.AGTR1_HUMAN Receptor for angiotensin II. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Publication Abstract from PubMed 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. Antibodies expand the scope of angiotensin receptor pharmacology.,Skiba MA, Sterling SM, Rawson S, Zhang S, Xu H, Jiang H, Nemeth GR, Gilman MSA, Hurley JD, Shen P, Staus DP, Kim J, McMahon C, Lehtinen MK, Rockman HA, Barth P, Wingler LM, Kruse AC Nat Chem Biol. 2024 May 14. doi: 10.1038/s41589-024-01620-6. PMID:38744986 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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