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      High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor.

      Science (New York, N.Y.)

      Static Electricity, metabolism, chemistry, Rhodopsin, Recombinant Fusion Proteins, Receptors, Adrenergic, beta-2, Protein Structure, Secondary, Protein Folding, Protein Conformation, Propanolamines, Muramidase, Models, Molecular, Ligands, Humans, Drug Inverse Agonism, Crystallography, X-Ray, Crystallization, Cholesterol, Cell Membrane, Binding Sites, enzymology, Bacteriophage T4

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          Abstract

          Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors constitute the largest family of eukaryotic signal transduction proteins that communicate across the membrane. We report the crystal structure of a human beta2-adrenergic receptor-T4 lysozyme fusion protein bound to the partial inverse agonist carazolol at 2.4 angstrom resolution. The structure provides a high-resolution view of a human G protein-coupled receptor bound to a diffusible ligand. Ligand-binding site accessibility is enabled by the second extracellular loop, which is held out of the binding cavity by a pair of closely spaced disulfide bridges and a short helical segment within the loop. Cholesterol, a necessary component for crystallization, mediates an intriguing parallel association of receptor molecules in the crystal lattice. Although the location of carazolol in the beta2-adrenergic receptor is very similar to that of retinal in rhodopsin, structural differences in the ligand-binding site and other regions highlight the challenges in using rhodopsin as a template model for this large receptor family.

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          Author and article information

          Journal
          10.1126/science.1150577
          2583103
          17962520

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