G-protein-coupled receptor inactivation by an allosteric inverse-agonist antibody
| Autor: | Simone Weyand, Yoshiko Nakada-Nakura, Chiyo Ikeda-Suno, Osamu Kusano-Arai, Takatoshi Arakawa, Takami Yurugi-Kobayashi, Takao Hamakubo, Tatsuro Shimamura, Norimichi Nomura, Tomoya Hino, So Iwata, Takeshi Murata, Takuya Kobayashi, Hiroko Iwanari, Alexander D. Cameron |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Agonist Drug Inverse Agonism Receptor Adenosine A2A Protein Conformation G protein medicine.drug_class Allosteric regulation Immune receptor Biology Ligands Pichia Article Receptors G-Protein-Coupled Immunoglobulin Fab Fragments Mice 03 medical and health sciences 0302 clinical medicine Allosteric Regulation medicine Animals Humans Inverse agonist Receptor 030304 developmental biology G protein-coupled receptor 0303 health sciences Multidisciplinary Opsins Antibodies Monoclonal Complementarity Determining Regions Adenosine receptor Molecular biology Biophysics 030217 neurology & neurosurgery |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/nature10750 |
| Popis: | 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 structure 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. |
| Databáze: | OpenAIRE |
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