3KJ6

Crystal structure of a Methylated beta2 Adrenergic Receptor-Fab complex

Summary for 3KJ6

• Entry DOI: 10.2210/pdb3kj6/pdb
• Descriptor: Beta-2 adrenergic receptor, Fab light chain, Fab heavy chain, ... (4 entities in total)
• Functional Keywords: transmembrane helices, cell membrane, disulfide bond, g-protein coupled receptor, glycoprotein, lipoprotein, membrane, palmitate, phosphoprotein, polymorphism, receptor, transducer, transmembrane, signaling protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane ; Multi- pass membrane protein : P07550
• Total number of polymer chains: 3
• Total formula weight: 88604.47

Authors

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. (deposition date: 2009-11-02, release date: 2010-02-16, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.4 Å)