8S4D
Crystal structure of a peptidergic GPCR in complex with a small synthetic G protein-biased agonist
This is a non-PDB format compatible entry.
Summary for 8S4D
| Entry DOI | 10.2210/pdb8s4d/pdb |
| Descriptor | Apelin receptor,Soluble cytochrome b562, (3~{S})-5-methyl-3-[[1-pentan-3-yl-2-(thiophen-2-ylmethyl)benzimidazol-5-yl]carbonylamino]hexanoic acid, OLEIC ACID, ... (5 entities in total) |
| Functional Keywords | receptor, gpcr, stabilised, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 1 |
| Total formula weight | 58646.47 |
| Authors | Verdon, G.,Currinn, H.,Solcan, N.,Schlenker, O.,Brown, A.J.H. (deposition date: 2024-02-21, release date: 2024-12-04, Last modification date: 2025-01-22) |
| Primary citation | Williams, T.L.,Verdon, G.,Kuc, R.E.,Currinn, H.,Bender, B.,Solcan, N.,Schlenker, O.,Macrae, R.G.C.,Brown, J.,Schutz, M.,Zhukov, A.,Sinha, S.,de Graaf, C.,Graf, S.,Maguire, J.J.,Brown, A.J.H.,Davenport, A.P. Structural and functional determination of peptide versus small molecule ligand binding at the apelin receptor. Nat Commun, 15:10714-10714, 2024 Cited by PubMed Abstract: We describe a structural and functional study of the G protein-coupled apelin receptor, which binds two endogenous peptide ligands, apelin and Elabela/Toddler (ELA), to regulate cardiovascular development and function. Characterisation of naturally occurring apelin receptor variants from the UK Genomics England 100,000 Genomes Project, and AlphaFold2 modelling, identifies T89 as important in the ELA binding site, and R168 as forming extensive interactions with the C-termini of both peptides. Base editing to introduce an R/H168 variant into human stem cell-derived cardiomyocytes demonstrates that this residue is critical for receptor binding and function. Additionally, we present an apelin receptor crystal structure bound to the G protein-biased, small molecule agonist, CMF-019, which reveals a deeper binding mode versus the endogenous peptides at lipophilic pockets between transmembrane helices associated with GPCR activation. Overall, the data provide proof-of-principle for using genetic variation to identify key sites regulating receptor-ligand engagement. PubMed: 39730334DOI: 10.1038/s41467-024-55381-w PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.584 Å) |
Structure validation
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