title: The structural basis for agonist and partial agonist action on a β(1)-adrenergic receptor.
abstract: 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) β(1)-adrenergic receptor (β(1)AR-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 (Ser(5.42) and Ser(5.46)), but partial agonists only interact with Ser(5.42) (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.
authors.affiliation: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
authors.forename: Tony
authors.initials: T
authors.lastname: Warne
authors.forename: Rouslan
authors.initials: R
authors.lastname: Moukhametzianov
authors.forename: Jillian G
authors.initials: JG
authors.lastname: Baker
authors.forename: Rony
authors.initials: R
authors.lastname: Nehmé
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Edwards
authors.forename: Andrew G W
authors.initials: AG
authors.lastname: Leslie
authors.forename: Gebhard F X
authors.initials: GF
authors.lastname: Schertler
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Tate
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D058671:Adrenergic beta-1 Receptor Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000420:Albuterol / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000662:Amphetamines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002395:Catecholamines / Q000378:metabolism; D018360:Crystallography, X-Ray; D004280:Dobutamine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D054333:Drug Partial Agonism; D006860:Hydrogen Bonding; D006912:Hydroxyquinolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007545:Isoproterenol / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D055550:Protein Stability / Q000187:drug effects; D018342:Receptors, Adrenergic, beta-1 / Q000737:chemistry* / Q000378:metabolism*; D012694:Serine / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014422:Turkeys
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D000662:Amphetamines; D002395:Catecholamines; D006912:Hydroxyquinolines; D008024:Ligands; D018342:Receptors, Adrenergic, beta-1; D004280:Dobutamine; D012694:Serine; C074413:carmoterol; D007545:Isoproterenol; D000420:Albuterol