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J. Biol. Chem., Vol. 265, Issue 28, 16891-16897, Oct, 1990

Characterization of the binding domain of the beta-adrenergic receptor with the fluorescent antagonist carazolol. Evidence for a buried ligand binding site

MR Tota and CD Strader
Department of Molecular Pharmacology and Biochemistry, Merck, Sharp, and Dohme Research Laboratories, Rahway, New Jersey 07065.

The antagonist carazolol has been used as a fluorescent probe for the binding site of the beta-adrenergic receptor (beta AR). The fluorescence properties of carazolol are dominated by the emission of the carbazole group, with the fine structure of the spectrum, but not the quantum yield, sensitive to the environment of the probe. The fluorescence emission spectrum of the bound probe is consistent with an extremely hydrophobic environment in the binding site of the receptor. Binding of carazolol to the purified beta AR increases the polarization of the fluorophore. Exposure to collisional quenchers has demonstrated the bound carazolol to be completely inaccessible to the solvent. Furthermore, the fluorescence of bound carazolol is not quenched by exposure to sodium nitrite, a Forster energy acceptor which has an R0 value of 11.7 A with carazolol. Thus, physical analysis of the binding site of the beta AR by carazolol fluorescence indicates that the antagonist binds to the beta AR in a rigid hydrophobic environment which is buried deep within the core of the protein.
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