3KJ6

Crystal structure of a Methylated beta2 Adrenergic Receptor-Fab complex

3KJ6 の概要

• エントリーDOI: 10.2210/pdb3kj6/pdb
• 分子名称: Beta-2 adrenergic receptor, Fab light chain, Fab heavy chain, ... (4 entities in total)
• 機能のキーワード: transmembrane helices, cell membrane, disulfide bond, g-protein coupled receptor, glycoprotein, lipoprotein, membrane, palmitate, phosphoprotein, polymorphism, receptor, transducer, transmembrane, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Cell membrane ; Multi- pass membrane protein : P07550
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 88604.47

構造登録者

Bokoch, M.P.,Zou, Y.,Rasmussen, S.G.F.,Liu, C.W.,Nygaard, R.,Rosenbaum, D.M.,Fung, J.J.,Choi, H.-J.,Thian, F.S.,Kobilka, T.S.,Puglisi, J.D.,Weis, W.I.,Pardo, L.,Prosser, S.,Mueller, L.,Kobilka, B.K. (登録日: 2009-11-02, 公開日: 2010-02-16, 最終更新日: 2024-11-06)

主引用文献

Bokoch, M.P.,Zou, Y.,Rasmussen, S.G.,Liu, C.W.,Nygaard, R.,Rosenbaum, D.M.,Fung, J.J.,Choi, H.J.,Thian, F.S.,Kobilka, T.S.,Puglisi, J.D.,Weis, W.I.,Pardo, L.,Prosser, R.S.,Mueller, L.,Kobilka, B.K.
Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor.
Nature, 463:108-112, 2010

PubMed Abstract: G-protein-coupled receptors (GPCRs) are seven-transmembrane proteins that mediate most cellular responses to hormones and neurotransmitters. They are the largest group of therapeutic targets for a broad spectrum of diseases. Recent crystal structures of GPCRs have revealed structural conservation extending from the orthosteric ligand-binding site in the transmembrane core to the cytoplasmic G-protein-coupling domains. In contrast, the extracellular surface (ECS) of GPCRs is remarkably diverse and is therefore an ideal target for the discovery of subtype-selective drugs. However, little is known about the functional role of the ECS in receptor activation, or about conformational coupling of this surface to the native ligand-binding pocket. Here we use NMR spectroscopy to investigate ligand-specific conformational changes around a central structural feature in the ECS of the beta(2) adrenergic receptor: a salt bridge linking extracellular loops 2 and 3. Small-molecule drugs that bind within the transmembrane core and exhibit different efficacies towards G-protein activation (agonist, neutral antagonist and inverse agonist) also stabilize distinct conformations of the ECS. We thereby demonstrate conformational coupling between the ECS and the orthosteric binding site, showing that drugs targeting this diverse surface could function as allosteric modulators with high subtype selectivity. Moreover, these studies provide a new insight into the dynamic behaviour of GPCRs not addressable by static, inactive-state crystal structures.

PubMed: 20054398
DOI: 10.1038/nature08650

実験手法

X-RAY DIFFRACTION (3.4 Å)