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Activation and allosteric modulation of a muscarinic acetylcholine receptor

Author

Listed:
  • Andrew C. Kruse

    (Stanford University School of Medicine, 279 Campus Drive)

  • Aaron M. Ring

    (Stanford University School of Medicine, 279 Campus Drive
    Stanford University School of Medicine, 299 Campus Drive)

  • Aashish Manglik

    (Stanford University School of Medicine, 279 Campus Drive)

  • Jianxin Hu

    (Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases)

  • Kelly Hu

    (Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases)

  • Katrin Eitel

    (Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangen, Germany)

  • Harald Hübner

    (Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangen, Germany)

  • Els Pardon

    (Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium
    Structural Biology Research Centre, VIB, Pleinlaan 2, B-1050 Brussels, Belgium)

  • Celine Valant

    (Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University)

  • Patrick M. Sexton

    (Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University)

  • Arthur Christopoulos

    (Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University)

  • Christian C. Felder

    (Neuroscience, Eli Lilly & Co.)

  • Peter Gmeiner

    (Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangen, Germany)

  • Jan Steyaert

    (Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium
    Structural Biology Research Centre, VIB, Pleinlaan 2, B-1050 Brussels, Belgium)

  • William I. Weis

    (Stanford University School of Medicine, 279 Campus Drive
    Stanford University School of Medicine, 299 Campus Drive)

  • K. Christopher Garcia

    (Stanford University School of Medicine, 279 Campus Drive
    Stanford University School of Medicine, 299 Campus Drive)

  • Jürgen Wess

    (Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases)

  • Brian K. Kobilka

    (Stanford University School of Medicine, 279 Campus Drive)

Abstract

Despite recent advances in crystallography and the availability of G-protein-coupled receptor (GPCR) structures, little is known about the mechanism of their activation process, as only the β2 adrenergic receptor (β2AR) and rhodopsin have been crystallized in fully active conformations. Here we report the structure of an agonist-bound, active state of the human M2 muscarinic acetylcholine receptor stabilized by a G-protein mimetic camelid antibody fragment isolated by conformational selection using yeast surface display. In addition to the expected changes in the intracellular surface, the structure reveals larger conformational changes in the extracellular region and orthosteric binding site than observed in the active states of the β2AR and rhodopsin. We also report the structure of the M2 receptor simultaneously bound to the orthosteric agonist iperoxo and the positive allosteric modulator LY2119620. This structure reveals that LY2119620 recognizes a largely pre-formed binding site in the extracellular vestibule of the iperoxo-bound receptor, inducing a slight contraction of this outer binding pocket. These structures offer important insights into the activation mechanism and allosteric modulation of muscarinic receptors.

Suggested Citation

  • Andrew C. Kruse & Aaron M. Ring & Aashish Manglik & Jianxin Hu & Kelly Hu & Katrin Eitel & Harald Hübner & Els Pardon & Celine Valant & Patrick M. Sexton & Arthur Christopoulos & Christian C. Felder &, 2013. "Activation and allosteric modulation of a muscarinic acetylcholine receptor," Nature, Nature, vol. 504(7478), pages 101-106, December.
  • Handle: RePEc:nat:nature:v:504:y:2013:i:7478:d:10.1038_nature12735
    DOI: 10.1038/nature12735
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    Cited by:

    1. Noriyuki Uchida & Ai Kohata & Kou Okuro & Annalisa Cardellini & Chiara Lionello & Eric A. Zizzi & Marco A. Deriu & Giovanni M. Pavan & Michio Tomishige & Takaaki Hikima & Takuzo Aida, 2022. "Reconstitution of microtubule into GTP-responsive nanocapsules," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Geng Chen & Jun Xu & Asuka Inoue & Maximilian F. Schmidt & Chen Bai & Qiuyuan Lu & Peter Gmeiner & Zheng Liu & Yang Du, 2022. "Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Yuxia Qian & Jiening Wang & Linlin Yang & Yanru Liu & Lina Wang & Wei Liu & Yun Lin & Hong Yang & Lixin Ma & Sheng Ye & Shan Wu & Anna Qiao, 2022. "Activation and signaling mechanism revealed by GPR119-Gs complex structures," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    4. Thomas Fontaine & Andreas Busch & Toon Laeremans & Stéphane De Cesco & Yi-Lynn Liang & Veli-Pekka Jaakola & Zara Sands & Sarah Triest & Simonas Masiulis & Lies Dekeyzer & Noor Samyn & Nicolas Loeys & , 2024. "Structure elucidation of a human melanocortin-4 receptor specific orthosteric nanobody agonist," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Yosuke Toyoda & Angqi Zhu & Fang Kong & Sisi Shan & Jiawei Zhao & Nan Wang & Xiaoou Sun & Linqi Zhang & Chuangye Yan & Brian K. Kobilka & Xiangyu Liu, 2023. "Structural basis of α1A-adrenergic receptor activation and recognition by an extracellular nanobody," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    6. Yang Yang & Hye Jin Kang & Ruogu Gao & Jingjing Wang & Gye Won Han & Jeffrey F. DiBerto & Lijie Wu & Jiahui Tong & Lu Qu & Yiran Wu & Ryan Pileski & Xuemei Li & Xuejun Cai Zhang & Suwen Zhao & Terry K, 2023. "Structural insights into the human niacin receptor HCA2-Gi signalling complex," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    7. Jun Yu & Amit Kumar & Xuefeng Zhang & Charlotte Martin & Kevin Van holsbeeck & Pierre Raia & Antoine Koehl & Toon Laeremans & Jan Steyaert & Aashish Manglik & Steven Ballet & Andreas Boland & Miriam S, 2024. "Structural basis of μ-opioid receptor targeting by a nanobody antagonist," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    8. Wessel A. C. Burger & Vi Pham & Ziva Vuckovic & Alexander S. Powers & Jesse I. Mobbs & Yianni Laloudakis & Alisa Glukhova & Denise Wootten & Andrew B. Tobin & Patrick M. Sexton & Steven M. Paul & Chri, 2023. "Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    9. Joshua A. Lees & João M. Dias & Francis Rajamohan & Jean-Philippe Fortin & Rebecca O’Connor & Jimmy X. Kong & Emily A. G. Hughes & Ethan L. Fisher & Jamison B. Tuttle & Gabrielle Lovett & Bethany L. K, 2023. "An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    10. Xiao Teng & Sijia Chen & Yingying Nie & Peng Xiao & Xiao Yu & Zhenhua Shao & Sanduo Zheng, 2022. "Ligand recognition and biased agonism of the D1 dopamine receptor," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

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