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G-protein-coupled receptor inactivation by an allosteric inverse-agonist antibody

机译：变构反激动剂抗体使G蛋白偶联受体失活

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摘要

G-protein-coupled receptors are the largest class of cell-surface receptors, and these membrane proteins exist in equilibrium between inactive and active states. Conformational changes induced by extracellular ligands binding to G-protein-coupled receptors result in a cellular response through the activation of G proteins. The A_(2A) adenosine receptor (A_(2A)AR) is responsible for regulating blood flow to the cardiac muscle and is important in the regulation of glutamate and dopamine release in the brain. Here we report the raising of a mouse monoclonal antibody against human A_(2A)AR that prevents agonist but not antagonist binding to the extracellular ligand-binding pocket, and describe the structure of A_(2A)AR in complex with the antibody Fab fragment (Fab2838). This structure reveals that Fab2838 recognizes the intracellular surface of A_(2A)AR and that its complementarity-determining region, CDR-H3, penetrates into the receptor. CDR-H3 is located in a similar position to the G-protein carboxy-terminal fragment in the active opsin structure1 and to CDR-3 of the nanobody in the active β_2-adrenergic receptor structure, but locks A_(2A)AR in an inactive conformation. These results suggest a new strategy to modulate the activity of G-protein-coupled receptors.
机译：G蛋白偶联受体是细胞表面受体的最大类别，这些膜蛋白在非活性状态和活性状态之间处于平衡状态。由细胞外配体与G蛋白偶联受体结合引起的构象变化通过激活G蛋白导致细胞反应。 A_（2A）腺苷受体（A_（2A）AR）负责调节流向心肌的血流量，并且在调节大脑中的谷氨酸和多巴胺释放中起重要作用。在这里我们报告了针对人A_（2A）AR的小鼠单克隆抗体的产生，该抗体可防止激动剂但不能与细胞外配体结合口袋结合，并且描述了与抗体Fab片段复合的A_（2A）AR的结构（ Fab2838）。该结构表明Fab2838识别A_（2A）AR的细胞内表面，并且其互补决定区CDR-H3渗透到受体中。 CDR-H3与主动视蛋白结构1中的G蛋白羧基末端片段和主动β_2-肾上腺素受体结构中纳米抗体的CDR-3位于相似的位置，但将A_（2A）AR锁定在非活性状态构象。这些结果表明调节G蛋白偶联受体活性的新策略。

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  • 来源
    《Nature》 |2012年第7384期|p.237-240|共4页
  • 作者

    Tomoya Hino; Takatoshi Arakawa; Hiroko Iwanari; Takami Yurugi-Kobayashi; Chiyo Ikeda-Suno; Yoshiko Nakada-Nakura; Osamu Kusano-Arai; Simone Weyand; Tatsuro Shimamura; Norimichi Nomura; Alexander D. Cameron; Takuya Kobayashi; Takao Hamakubo; So Iwata; Takeshi Murata;

  • 作者单位

    Iwata Human Receptor Crystallography Project, ERATO, Japan Science and Technology Agency, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan,Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan, Department of Biotechnology, Graduate School of Engineering, Tottori University, 4-101, Koyama-cho minami, Tottori, 680-8552, Japan;

    Iwata Human Receptor Crystallography Project, ERATO, Japan Science and Technology Agency, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan,Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan;

    Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan;

    Iwata Human Receptor Crystallography Project, ERATO, Japan Science and Technology Agency, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan,Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan;

    Iwata Human Receptor Crystallography Project, ERATO, Japan Science and Technology Agency, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan,Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan;

    Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan,Perseus Proteomics Inc, 4-7-6 Komaba, Meguro, Tokyo 153-0041, Japan;

    Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan,Institute of Immunology Co. Ltd, 1-1-10 Koraku, Bunkyo, Tokyo 112-0004, Japan;

    Iwata Human Receptor Crystallography Project, ERATO, Japan Science and Technology Agency, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan,Division of Molecular Bioscience, Membrane Protein Crystallography Group, Imperial College London, Exhibition Road, London SW7 2AZ, UK,Membrane Protein Laboratory, Diamond Light Source, Harwell Science and Innovation Campus, Chilton, Didcot OX11 0DE, UK,Research Complex at Harwell, Rutherford Appleton Laboratory, Harwell Oxford, Didcot OX11 0FA, UK;

    Iwata Human Receptor Crystallography Project, ERATO, Japan Science and Technology Agency, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan,Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan;

    Iwata Human Receptor Crystallography Project, ERATO, Japan Science and Technology Agency, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan,Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan;

    Iwata Human Receptor Crystallography Project, ERATO, Japan Science and Technology Agency, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan,Division of Molecular Bioscience, Membrane Protein Crystallography Group, Imperial College London, Exhibition Road, London SW7 2AZ, UK,Membrane Protein Laboratory, Diamond Light Source, Harwell Science and Innovation Campus, Chilton, Didcot OX11 0DE, UK,Research Complex at Harwell, Rutherford Appleton Laboratory, Harwell Oxford, Didcot OX11 0FA, UK;

    Iwata Human Receptor Crystallography Project, ERATO, Japan Science and Technology Agency, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan,Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan,Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Kyoto University Faculty of Medicine, Kyoto 606-8501, Japan;

    Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan;

    Iwata Human Receptor Crystallography Project, ERATO, Japan Science and Technology Agency, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan,Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan,Division of Molecular Bioscience, Membrane Protein Crystallography Group, Imperial College London, Exhibition Road, London SW7 2AZ, UK,Membrane Protein Laboratory, Diamond Light Source, Harwell Science and Innovation Campus, Chilton, Didcot OX11 0DE, UK,Research Complex at Harwell, Rutherford Appleton Laboratory, Harwell Oxford, Didcot OX11 0FA, UK, Systems and Structural Biology Center, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan;

    Iwata Human Receptor Crystallography Project, ERATO, Japan Science and Technology Agency, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan,Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan, Systems and Structural Biology Center, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan, Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage, Chiba 263-8522, Japan;

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