9ZXD
Structure of AT118-R nanobody in complex with the angiotensin II type I receptor bound to L-162,313
This is a non-PDB format compatible entry.
Summary for 9ZXD
| Entry DOI | 10.2210/pdb9zxd/pdb |
| EMDB information | 74920 |
| Descriptor | AT118-R nanobody,Type-1 angiotensin II receptor with Soluble cytochrome b562 insertion, BAG2 Anti-BRIL Fab Heavy Chain, BAG2 Anti-BRIL Fab Light Chain, ... (5 entities in total) |
| Functional Keywords | gpcr, nanobody, membrane protein |
| Biological source | synthetic construct More |
| Total number of polymer chains | 3 |
| Total formula weight | 114539.80 |
| Authors | Skiba, M.A.,Kruse, A.C. (deposition date: 2026-01-03, release date: 2026-07-29, Last modification date: 2026-08-12) |
| Primary citation | Skiba, M.A.,Liu, J.,Shen, P.,Kim, J.,Wren, E.,Gilman, M.S.A.,Staus, D.,McMahon, C.,Smith, J.S.,Lefkowitz, R.J.,Kahne, D.,Wingler, L.M.,Kruse, A.C. Activation of the angiotensin II type I receptor by a nonpeptide agonist. Proc.Natl.Acad.Sci.USA, 123:e2602538123-e2602538123, 2026 Cited by PubMed Abstract: The angiotensin II type I receptor (AT1R) is a G protein-coupled receptor that regulates the cardiovascular system and as a result is one of the most successful pharmacological targets for the treatment of hypertension. Within the angiotensin receptor pharmacological landscape, agonists are peptide ligands, whereas potent antagonists are predominantly small molecules. Three decades ago, a small number of nonpeptide AT1R agonists were identified. These molecules largely share a chemical scaffold with AT1R antagonists, but appeared to interact with the receptor in a manner that diverges from both antagonists and peptide agonists. Here, we revisit L-162,313, the prototype nonpeptide AT1R agonist and determine how the antagonist-like chemical scaffold acts as an agonist. L-162,313 binds similarly to AT1R antagonists, but unlike antagonists, it engages the same activation switches as peptide agonists. We map the spatial relationship required for activation of AT1R by nonpeptide agonists and used this information to design a small library of L-162,313 derivatives. These rationally designed derivatives had the expected reduced or enhanced potency based on the structural basis for activation. Our data resolve a long-standing pharmacological mystery and provide a foundation for generating more efficacious small molecule AT1R agonists. PubMed: 42550893DOI: 10.1073/pnas.2602538123 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.2 Å) |
Structure validation
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