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.
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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] |
Citation:
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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