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

Nature volume 469, pages 241–244 (2011)Cite this article

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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 noradrenaline1,2. 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 numbering3). 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.

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Figure 1: Structure of the β 1 -adrenergic receptor bound to agonists.
Figure 2: Polar and non-polar interactions involved in agonist binding to β 1 -adrenergic receptor.
Figure 3: Comparison of the ligand-binding pockets of the β 1 and β 2 adrenergic receptors.
Figure 4: Differences in the ligand-binding pocket between antagonist- and agonist-bound β 1 -adrenergic receptor.

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Primary accessions

Protein Data Bank

Data deposits

Coordinates and structure factors have been submitted to the Protein Data Bank under accession codes 2y00, 2y01, 2y02, 2y03 and 2y04 for β44-m23 bound either to dobutamine (dob92 and dob102), carmoterol, isoprenaline or salbutamol, respectively.

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Acknowledgements

This work was supported by core funding from the MRC and the BBSRC grant (BB/G003653/1). Financial support for G.F.X.S was also from a Human Frontier Science Project (HFSP) programme grant (RG/0052), a European Commission FP6 specific targeted research project (LSH-2003-1.1.0-1) and an ESRF long-term proposal. J.G.B. was funded by a Wellcome Trust Clinician Scientist Fellowship. We are grateful to P. Coli and A. Rizzi for the supply of (R,R)-carmoterol. F. Gorrec is thanked for his help with crystallisation robotics. We would also like to thank beamline staff at the European Synchrotron Radiation Facility, particularly D. Flot and A. Popov at ID23-2 and F. Marshall, M. Weir, M. Congreve and R. Henderson for comments on the manuscript.

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Author notes

  1. Gebhard F. X. Schertler

    Present address: Present address: Paul Scherrer Institut, Laboratory of Biomolecular Research, BMR, OFLC 109, CH-5232 Villigen PSI, Switzerland.,

Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK ,

    Tony Warne, Rouslan Moukhametzianov, Rony Nehmé, Patricia C. Edwards, Andrew G. W. Leslie, Gebhard F. X. Schertler & Christopher G. Tate

  2. Institute of Cell Signalling, C Floor Medical School, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK ,

    Jillian G. Baker

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Contributions

T.W. devised and performed receptor expression, purification, crystallization, cryo-cooling of the crystals, data collection and initial data processing. P.C.E. helped with crystal cryo-cooling and data collection. J.G.B. performed the pharmacological analyses on receptor mutants in whole cells and R.N. performed the ligand binding studies on baculovirus-expressed receptors. R.M. and A.G.W.L. were involved in data processing and structure refinement. Manuscript preparation was performed by T.W., C.G.T., A.G.W.L. and G.F.X.S. The overall project management was by G.F.X.S. and C.G.T.

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Correspondence to Gebhard F. X. Schertler or Christopher G. Tate.

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The authors declare no competing financial interests.

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Warne, T., Moukhametzianov, R., Baker, J. et al. The structural basis for agonist and partial agonist action on a β1-adrenergic receptor. Nature 469, 241–244 (2011). https://doi.org/10.1038/nature09746

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