text: Drug-protein interactions: isolation and characterization of covalent adducts of phenoxybenzamine and calmodulin.
  Phenoxybenzamine, an alpha-adrenergic antagonist containing a (chloroethyl)amine group, labels calmodulin in the presence of calcium. The covalent interaction is inhibited by chlorpromazine in a concentration-dependent manner. Adducts of calmodulin and phenoxybenzamine were separated by high-performance liquid chromatography into four major fractions: two containing 0.6 and 1.2 mol of drug per mol of protein and two different fractions each containing 2.0 mol/mol. Each adduct had a reduced ability to activate cyclic nucleotide phosphodiesterase and myosin light chain kinase, and the chlorpromazine binding capacities of the phenoxybenzamine-calmodulin adducts were diminished to the extent of phenoxybenzamine incorporation into each adduct. Isolation and characterization of labeled peptides from phenoxybenzamine-modified calmodulins indicated that peptides encompassing residues 38-75, 107-126, and 127-148 contained phenoxybenzamine label. These studies directly demonstrate the relatedness between the binding activities of two structurally dissimilar calmodulin antagonists, demonstrate that covalent adducts of calmodulin and drugs with equal stoichiometries of labeling can have quantitative differences in activity and sites of modification, and provide direct evidence of distinct drug binding regions in calmodulin located in the amphipathic alpha-helical regions of the second and fourth domains.
entities.id: T10 T11 T12 T13 T14 T15 T16 T17 T18 T19 T1 T20 T21 T22 T2 T3 T4 T5 T6 T7 T8 T9
entities.type: CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-Y GENE-Y CHEMICAL GENE-Y GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
entities.text: phenoxybenzamine phenoxybenzamine phenoxybenzamine calmodulin calmodulin calmodulin calmodulin cyclic nucleotide phosphodiesterase myosin light chain kinase calmodulin Phenoxybenzamine calmodulins calmodulin calmodulin calcium chlorpromazine phenoxybenzamine cyclic nucleotide chlorpromazine (chloroethyl)amine phenoxybenzamine phenoxybenzamine