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Department of Energy Office of Science
GM/CA @ APS Sponsors:
National Institute of General Medical Sciences (NIGMS) and National Cancer Institute (NCI) of the National Institutes of Health (NIH)

Beta adrenergic receptors

Brian Kobilka and Bill Weis groups (Stanford University) and collaborators


The groups of Brian Kobilka and Bill Weis at Stanford University made new advances in very challenging membrane-protein studies of beta adrenergic receptors, which represent the largest group of targets for pharmaceuticals. These receptors mediate most cell responses to extracellular hormones and neurotransmitters, resulting in activation of G proteins that change the level of intracellular messengers, such as Ca2+, cAMP, or signaling lipids. How ligand binding to the extracellular surface leads to transmembrane signal transduction has been unclear. Structures of inhibited states (with bound inverse-agonist ligands) of beta2 adrenergic receptors were determined previously using the mini-beam and rastering capabilities at GM/CA-CAT; comparison of these to the structure of an inhibited beta1 adrenergic receptor show that their orthosteric binding pockets are nearly identical in sequence, but side chains in important extracellular loops 2 and 3 (ECL2, ECL3) are only ~50% identical in sequence. The chemical environment of a salt link between ECL3 Lys 305 and ECL2 Asp 192 was probed by NMR under different ligand-binding conditions. A crystal structure from data taken at GM/CA provided a structural foundation and important control to show that 13C labeling of Lys 305 did not alter the protein structure. The NMR studies revealed that small-molecule drugs that serve as agonists, neutral antagonists, and inverse agonists stabilize distinct conformations of the extracellular surface, and provide conformational coupling between the surface and the orthosteric binding site.

Figure: (A) extracellular surface of carazolol-bound (inverse agonist) beta2 adrenergic receptor, with cyan ECL2, dark blue ECL3, magenta Lys 305, yellow Asp 192, and green carazolol, (B) detailed intramolecular and ligand-binding interactions with transmembrane helices 1 and 2 omitted for clarity. [Figure reprinted by permission from Macmillan Publishers Ltd: Nature, copyright 2010]


Bokoch, MP, Zou, Y, Rasmussen, SGF, Liu, CW, Nygaard, R, Rosenbaum, DM, Fung, JJ, Choi, H-J, Thian, FS, Kobilka, TS, Puglisi, JD, Weis, WI, Pardo, L, Prosser, RS, Mueller, L, Kobilka, BK. Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor, Nature 463, 108-112 (2010). DOI: 10.1038/nature08650

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