G-protein-coupled receptor inactivation by an allosteric inverse-agonist antibody.
G-protein-coupled receptor inactivation by an allosteric inverse-agonist antibody.
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DOI：
10.1038/nature10750
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发表时间：
2012-01-29
期刊：
影响因子：
64.8
通讯作者：
Murata, Takeshi
中科院分区：
文献类型：
--
作者：
Hino, Tomoya;Arakawa, Takatoshi;Iwanari, Hiroko;Yurugi-Kobayashi, Takami;Ikeda-Suno, Chiyo;Nakada-Nakura, Yoshiko;Kusano-Arai, Osamu;Weyand, Simone;Shimamura, Tatsuro;Nomura, Norimichi;Cameron, Alexander D.;Kobayashi, Takuya;Hamakubo, Takao;Iwata, So;Murata, Takeshi
G蛋白偶联受体（GPCRs）是最大的一类细胞表面受体，这些膜蛋白在非活性和活性状态之间处于平衡。细胞外配体与GPCRs结合所诱导的构象变化通过G蛋白的激活导致细胞反应。A2A腺苷受体（A2AAR）负责调节流向心肌的血流，并且在大脑中谷氨酸和多巴胺释放的调节中起重要作用。在这项研究中，我们成功地制备了一种针对人A2AAR的小鼠单克隆抗体，该抗体可阻止激动剂但不阻止拮抗剂与细胞外配体结合口袋结合。A2AAR - 抗体Fab片段（Fab2838）复合物的结构显示，该片段出乎意料地识别A2AAR的细胞内表面，并且其互补决定区CDR - H3穿透进入受体。CDR - H3位于与活性视蛋白结构中的G蛋白C末端片段以及活性β2肾上腺素能受体结构中的纳米抗体的CDR - 3相似的位置，但将A2AAR锁定在非活性构象。这些结果为调节GPCR活性的新策略提供了思路。
G protein-coupled receptors (GPCRs) 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 GPCRs result in a cellular response through the activation of G-proteins. The A2A adenosine receptor (A2AAR) is responsible for regulating blood flow to the cardiac muscle and is important in the regulation of glutamate and dopamine release in the brain. In this study, we have successfully raised a mouse monoclonal antibody against human A2AAR that prevents agonist but not antagonist binding to the extracellular ligand-binding pocket. The structure of the A2AAR-antibody Fab fragment (Fab2838) complex reveals that the fragment, unexpectedly, recognises the intracellular surface of A2AAR and that its complementarity determining region, CDR-H3, penetrates into the receptor. CDR-H3 is located in a similar position to the G-protein C-terminal fragment in the active opsin structure and to the CDR-3 of the nanobody in the active β2 adrenergic receptor structure but locks the A2AAR in an inactive conformation. These results shed light on a novel strategy to modulate GPCR activity.
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影响因子：
64.8
作者：
Scheerer, Patrick;Park, Jung Hee;Ernst, Oliver P.
通讯作者：
Ernst, Oliver P.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
强大的体积溶剂校正和各向异性缩放程序。
DOI：
10.1107/s0907444905007894
发表时间：
2005-07
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Afonine PV;Grosse-Kunstleve RW;Adams PD
通讯作者：
Adams PD
影响因子：
3.4
作者：
Mueller, Christa E.;Jacobson, Kenneth A.
通讯作者：
Jacobson, Kenneth A.
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC