3VG9

Crystal structure of human adenosine A2A receptor with an allosteric inverse-agonist antibody at 2.7 A resolution

Summary for 3VG9

• Entry DOI: 10.2210/pdb3vg9/pdb
• Related: 3VGA
• Descriptor: Adenosine receptor A2a, antibody fab fragment light chain, antibody fab fragment heavy chain, ... (7 entities in total)
• Functional Keywords: 7 transmembrane receptor, signal transduction, signaling protein
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P29274
• Total number of polymer chains: 3
• Total formula weight: 86917.91

Authors

Hino, T.,Arakawa, T.,Iwanari, H.,Yurugi-Kobayashi, T.,Ikeda-Suno, C.,Nakada-Nakura, Y.,Kusano-Arai, O.,Weyand, S.,Shimamura, T.,Nomura, N.,Cameron, A.D.,Kobayashi, T.,Hamakubo, T.,Iwata, S.,Murata, T. (deposition date: 2011-08-04, release date: 2012-02-01, Last modification date: 2023-11-08)

Primary citation

Hino, T.,Arakawa, T.,Iwanari, H.,Yurugi-Kobayashi, T.,Ikeda-Suno, C.,Nakada-Nakura, Y.,Kusano-Arai, O.,Weyand, S.,Shimamura, T.,Nomura, N.,Cameron, A.D.,Kobayashi, T.,Hamakubo, T.,Iwata, S.,Murata, T.
G-protein-coupled receptor inactivation by an allosteric inverse-agonist antibody
Nature, 482:237-240, 2012

PubMed Abstract: 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.

PubMed: 22286059
DOI: 10.1038/nature10750

Experimental method

X-RAY DIFFRACTION (2.7 Å)