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Structure of a β1-adrenergic G-protein-coupled receptor

Author

Listed:
  • Tony Warne

    (MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK)

  • Maria J. Serrano-Vega

    (MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK)

  • Jillian G. Baker

    (Institute of Cell Signalling, Medical School, Queen’s Medical Centre, University of Nottingham)

  • Rouslan Moukhametzianov

    (MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK)

  • Patricia C. Edwards

    (MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK)

  • Richard Henderson

    (MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK)

  • Andrew G. W. Leslie

    (MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK)

  • Christopher G. Tate

    (MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK)

  • Gebhard F. X. Schertler

    (MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK)

Abstract

G-protein-coupled receptors have a major role in transmembrane signalling in most eukaryotes and many are important drug targets. Here we report the 2.7 Å resolution crystal structure of a β1-adrenergic receptor in complex with the high-affinity antagonist cyanopindolol. The modified turkey (Meleagris gallopavo) receptor was selected to be in its antagonist conformation and its thermostability improved by earlier limited mutagenesis. The ligand-binding pocket comprises 15 side chains from amino acid residues in 4 transmembrane α-helices and extracellular loop 2. This loop defines the entrance of the ligand-binding pocket and is stabilized by two disulphide bonds and a sodium ion. Binding of cyanopindolol to the β1-adrenergic receptor and binding of carazolol to the β2-adrenergic receptor involve similar interactions. A short well-defined helix in cytoplasmic loop 2, not observed in either rhodopsin or the β2-adrenergic receptor, directly interacts by means of a tyrosine with the highly conserved DRY motif at the end of helix 3 that is essential for receptor activation.

Suggested Citation

  • Tony Warne & Maria J. Serrano-Vega & Jillian G. Baker & Rouslan Moukhametzianov & Patricia C. Edwards & Richard Henderson & Andrew G. W. Leslie & Christopher G. Tate & Gebhard F. X. Schertler, 2008. "Structure of a β1-adrenergic G-protein-coupled receptor," Nature, Nature, vol. 454(7203), pages 486-491, July.
    • Handle: RePEc:nat:nature:v:454:y:2008:i:7203:d:10.1038_nature07101
    DOI: 10.1038/nature07101
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    Cited by:

    1. Yun Zhu & Bo-Ji Peng & Smriti Kumar & Lauren Stover & Jing-Yuan Chang & Jixing Lyu & Tianqi Zhang & Samantha Schrecke & Djavdat Azizov & David H. Russell & Lei Fang & Arthur Laganowsky, 2023. "Polyamine detergents tailored for native mass spectrometry studies of membrane proteins," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    2. Minfei Su & Navid Paknejad & Lan Zhu & Jinan Wang & Hung Nguyen Do & Yinglong Miao & Wei Liu & Richard K. Hite & Xin-Yun Huang, 2022. "Structures of β1-adrenergic receptor in complex with Gs and ligands of different efficacies," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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