The structural basis for agonist and partial agonist action on a β1-adrenergic receptor

By Tony Warne, R. Moukhametzianov, J. Baker, Rony Nehmé, P. Edwards, A. Leslie, G. Schertler, C. Tate. Nature, 2011

665 citations recorded by the source corpus.

β-adrenergic receptors (βARs) are G-protein-coupled receptors (GPCRs) that activate intracellular G proteins upon binding catecholamine agonist ligands such as adrenaline and noradrenaline. Synthetic ligands have been developed that either activate or inhibit βARs for the treatment of asthma, hypertension or cardiac dysfunction. These ligands are classified as either full agonists, partial agonists or antagonists, depending on whether the cellular response is similar to that of the native ligand, reduced or inhibited, respectively. However, the structural basis for these different ligand efficacies is unknown. Here we present four crystal structures of the thermostabilized turkey (Meleagris gallopavo) β1-adrenergic receptor (β1AR-m23) bound to the full agonists carmoterol and isoprenaline and the partial agonists salbutamol and dobutamine. In each case, agonist binding induces a 1 Å contraction of the catecholamine-binding pocket relative to the antagonist bound receptor. Full agonists can form hydrogen bonds with two conserved serine residues in transmembrane helix 5 (Ser5.42 and Ser5.46), but partial agonists only interact with Ser5.42 (superscripts refer to Ballesteros–Weinstein numbering). The structures provide an understanding of the pharmacological differences between different ligand classes, illuminating how GPCRs function and providing a solid foundation for the structure-based design of novel ligands with predictable efficacies.

Subfields: Animal Science and Zoology, Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/70f98845c96359dbf979316b115d61b9d15c03ef

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Citations in the corpus

Multiple conformational states in retrospective virtual screening – homology models vs. crystal structures: beta-2 adrenergic receptor case study (2015, neutral): “Beta1R 2Y00 [26] 2.”
The Molecular Basis of G Protein–Coupled Receptor Activation (2018, result): “Similar results were reported for β1AR bound to various partial and full agonists (45).”
A Structural Framework for GPCR Chemogenomics: What's In a Residue Number? (2018, neutral): “3 Bulges and constrictions in GPCR crystal structures determining the structure of ligand binding sites: H1 (PDB: 3RZE [25]), CXCR4 (PDB: 3ODU [26]), β1 (PDB: 2Y00 [23]), SMO (PDB: 4N4W [19]), mGlu1 (PDB: 4OR2 [32]), CRF1 (PDB: 4Z9G [31]), mGlu5 (PDB: 5CGD [34]).”
Loss of constitutive activity is correlated with increased thermostability of the human adenosine A2A receptor (2013, background): “The thermostabilized turkey b1 adrenoceptor was subsequently successfully crystallized, and a number of highresolution structures solved (Warne et al., 2008; 2011).”
Lifting the lid on GPCRs: the role of extracellular loops (2011, background): “For the b1AR, there are crystal structures for three antagonists (cyanopindolol, iodocyanopindolol and carazolol) (Warne et al., 2008; Moukhametzianov et al., 2011), two partial agonists (salbutamol and dobutamine) and two full agonists (carmoterol and isoprenaline) (Warne et al., 2011).”
GOMoDo: A GPCRs Online Modeling and Docking Webserver (2013, methodology): “The structure of the hβ2AR (UniProt ID: P07550) was modeled using as a template the structure of the turkey beta-1 adrenergic (tβ1AR) receptor (PDB entry: 2Y00 [45], UniProt ID: P07700).”