Structure of a β1-adrenergic G protein-coupled receptor
By Tony Warne, M. Serrano-Vega, J. Baker, R. Moukhametzianov, P. Edwards, R. Henderson, A. Leslie, C. Tate, G. Schertler. Nature, 2008
1,189 citations recorded by the source corpus.
G-protein-coupled receptors have a major role in transmembrane signalling in most eukaryotes and many are important drug targets. Here we report the 2.7 Å resolution crystal structure of a β1-adrenergic receptor in complex with the high-affinity antagonist cyanopindolol. The modified turkey (Meleagris gallopavo) receptor was selected to be in its antagonist conformation and its thermostability improved by earlier limited mutagenesis. The ligand-binding pocket comprises 15 side chains from amino acid residues in 4 transmembrane α-helices and extracellular loop 2. This loop defines the entrance of the ligand-binding pocket and is stabilized by two disulphide bonds and a sodium ion. Binding of cyanopindolol to the β1-adrenergic receptor and binding of carazolol to the β2-adrenergic receptor involve similar interactions. A short well-defined helix in cytoplasmic loop 2, not observed in either rhodopsin or the β2-adrenergic receptor, directly interacts by means of a tyrosine with the highly conserved DRY motif at the end of helix 3 that is essential for receptor activation.
Subfields: Molecular Biology, Spectroscopy
View Paper: https://www.semanticscholar.org/paper/841640e29fc43aa563aed274ff02b75e8f5798b4
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In Molecular Biology
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In Spectroscopy
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Citations in the corpus
- Twenty years on: the impact of fragments on drug discovery (2016, background): “The recent success in stabilizing GPCRs has generated proteins that are suitable for biophysical study, including fragment screening 89,90 .”
- Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment (2011, neutral): “…efforts: bovine rhodopsin (bRho) in liganded (Palczewski et al., 2000) and ligand-free (opsin) (Park et al., 2008; Scheerer et al., 2008) forms; human b2 (Cherezov et al., 2007) and turkey b1 (Warne et al., 2008) adrenergic receptors; and human A2A adenosine receptor (A2AAR) (Jaakola et al., 2008).”
- Outcome of a Workshop on Applications of Protein Models in Biomedical Research (2009, background): “Clearly, the recent GPCR structures (Cherezov et al., 2007; Rasmussen et al., 2007; Warne et al., 2008) will further aid modeling of this important class of biological targets.”
- Structure-based drug discovery and protein targets in the CNS. (2011, methodology): “The recent breakthroughs are described in more detail below, but in summary have introduced mutations (Warne et al., 2008), an additional domain (Cherezov et al., 2007) or complexation with antibody (Rosenbaum et al., 2007).”
- Lifting the lid on GPCRs: the role of extracellular loops (2011, background): “For the b1AR, there are crystal structures for three antagonists (cyanopindolol, iodocyanopindolol and carazolol) (Warne et al., 2008; Moukhametzianov et al., 2011), two partial agonists (salbutamol and dobutamine) and two full agonists (carmoterol and isoprenaline) (Warne et al., 2011).”
- New design strategies for antidepressant drugs (2013, background): “Crystal structures for the b1-adrenergic, DA D3, 5-HT1B and 5-HT2B receptors have been reported in the last 5 years [58-60].”