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Crystal structure of the human β2 adrenergic G-protein-coupled receptor

Author

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  • Søren G. F. Rasmussen

    (Department of Molecular and Cellular Physiology and,)

  • Hee-Jung Choi

    (Department of Molecular and Cellular Physiology and,
    Stanford University School of Medicine, 279 Campus Drive, Stanford, Palo Alto, California 94305, USA)

  • Daniel M. Rosenbaum

    (Department of Molecular and Cellular Physiology and,)

  • Tong Sun Kobilka

    (Department of Molecular and Cellular Physiology and,)

  • Foon Sun Thian

    (Department of Molecular and Cellular Physiology and,)

  • Patricia C. Edwards

    (MRC Laboratory of Molecular Biology)

  • Manfred Burghammer

    (European Synchrotron Radiation Facility, 6 rue Jules Horowitz, BP220, 38043 Grenoble, cedex 9, France)

  • Venkata R. P. Ratnala

    (Department of Molecular and Cellular Physiology and,)

  • Ruslan Sanishvili

    (Argonne National Laboratory, GM/CA-CAT, Boulevard 436, D007, 9700 South Cass Avenue, Argonne, Illinois 60439, USA)

  • Robert F. Fischetti

    (Argonne National Laboratory, GM/CA-CAT, Boulevard 436, D007, 9700 South Cass Avenue, Argonne, Illinois 60439, USA)

  • Gebhard F. X. Schertler

    (MRC Laboratory of Molecular Biology)

  • William I. Weis

    (Department of Molecular and Cellular Physiology and,
    Stanford University School of Medicine, 279 Campus Drive, Stanford, Palo Alto, California 94305, USA)

  • Brian K. Kobilka

    (Department of Molecular and Cellular Physiology and,)

Abstract

Structural analysis of G-protein-coupled receptors (GPCRs) for hormones and neurotransmitters has been hindered by their low natural abundance, inherent structural flexibility, and instability in detergent solutions. Here we report a structure of the human β2 adrenoceptor (β2AR), which was crystallized in a lipid environment when bound to an inverse agonist and in complex with a Fab that binds to the third intracellular loop. Diffraction data were obtained by high-brilliance microcrystallography and the structure determined at 3.4 Å/3.7 Å resolution. The cytoplasmic ends of the β2AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the β2AR are not seen. The β2AR structure differs from rhodopsin in having weaker interactions between the cytoplasmic ends of transmembrane (TM)3 and TM6, involving the conserved E/DRY sequences. These differences may be responsible for the relatively high basal activity and structural instability of the β2AR, and contribute to the challenges in obtaining diffraction-quality crystals of non-rhodopsin GPCRs.

Suggested Citation

  • Søren G. F. Rasmussen & Hee-Jung Choi & Daniel M. Rosenbaum & Tong Sun Kobilka & Foon Sun Thian & Patricia C. Edwards & Manfred Burghammer & Venkata R. P. Ratnala & Ruslan Sanishvili & Robert F. Fisch, 2007. "Crystal structure of the human β2 adrenergic G-protein-coupled receptor," Nature, Nature, vol. 450(7168), pages 383-387, November.
    • Handle: RePEc:nat:nature:v:450:y:2007:i:7168:d:10.1038_nature06325
    DOI: 10.1038/nature06325
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    Cited by:

    1. Nobuyoshi Nagamine & Takayuki Shirakawa & Yusuke Minato & Kentaro Torii & Hiroki Kobayashi & Masaya Imoto & Yasubumi Sakakibara, 2009. "Integrating Statistical Predictions and Experimental Verifications for Enhancing Protein-Chemical Interaction Predictions in Virtual Screening," PLOS Computational Biology, Public Library of Science, vol. 5(6), pages 1-11, June.
    2. Valérie Boivin-Jahns & Kerstin Uhland & Hans-Peter Holthoff & Niklas Beyersdorf & Vladimir Kocoski & Thomas Kerkau & Götz Münch & Martin J Lohse & Martin Ungerer & Roland Jahns, 2018. "Cyclopeptide COR-1 to treat beta1-adrenergic receptor antibody-induced heart failure," PLOS ONE, Public Library of Science, vol. 13(8), pages 1-23, August.
    3. Valérie Capra & Marta Busnelli & Alessandro Perenna & Manuela Ambrosio & Maria Rosa Accomazzo & Celine Galés & Bice Chini & G Enrico Rovati, 2013. "Full and Partial Agonists of Thromboxane Prostanoid Receptor Unveil Fine Tuning of Receptor Superactive Conformation and G Protein Activation," PLOS ONE, Public Library of Science, vol. 8(3), pages 1-12, March.
    4. Holly J Atkinson & John H Morris & Thomas E Ferrin & Patricia C Babbitt, 2009. "Using Sequence Similarity Networks for Visualization of Relationships Across Diverse Protein Superfamilies," PLOS ONE, Public Library of Science, vol. 4(2), pages 1-14, February.

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