2Y02

TURKEY BETA1 ADRENERGIC RECEPTOR WITH STABILISING MUTATIONS AND BOUND AGONIST CARMOTEROL

Summary for 2Y02

• Entry DOI: 10.2210/pdb2y02/pdb
• Related: 1DEP 2VT4 2Y00 2Y01 2Y03 2Y04
• Descriptor: BETA-1 ADRENERGIC RECEPTOR, CHOLESTEROL HEMISUCCINATE, HEGA-10, ... (6 entities in total)
• Functional Keywords: receptor, g protein coupled receptor, seven-helix receptor, integral membrane protein, thermostabilising point mutations, gpcr
• Biological source: MELEAGRIS GALLOPAVO (TURKEY)
• Total number of polymer chains: 2
• Total formula weight: 78383.19

Authors

Warne, A.,Moukhametzianov, R.,Baker, J.G.,Nehme, R.,Edwards, P.C.,Leslie, A.G.W.,Schertler, G.F.X.,Tate, C.G. (deposition date: 2010-11-30, release date: 2011-01-12, Last modification date: 2023-12-20)

Primary citation

Warne, A.,Moukhametzianov, R.,Baker, J.G.,Nehme, R.,Edwards, P.C.,Leslie, A.G.W.,Schertler, G.F.X.,Tate, C.G.
The Structural Basis for Agonist and Partial Agonist Action on a Beta1-Adrenergic Receptor
Nature, 469:241-, 2011

PubMed 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.

PubMed: 21228877
DOI: 10.1038/NATURE09746

Experimental method

X-RAY DIFFRACTION (2.6 Å)