Selective binding of ligands to beta 1, beta 2 or chimeric beta 1/beta 2-adrenergic receptors involves multiple subsites

EMBO J. 1990 May;9(5):1471-6.


The molecular basis of ligand binding selectivity to beta-adrenergic receptor subtypes was investigated by designing chimeric beta 1/beta 2-adrenergic receptors. These molecules consisted of a set of reciprocal constructions, obtained by the exchange between the wild-type receptor genes of one to three unmodified transmembrane regions, together with their extracellular flanking regions. Eight different chimeras were expressed in Escherichia coli and studied with selective beta-adrenergic ligands. The evaluation of the relative effect of each chimeric exchange on ligand binding affinity was based on the analysis of delta G values, calculated from the equilibrium binding constants, as a function of the number of substituted beta 2-adrenergic receptor transmembrane domains. The data showed that the contribution of each exchanged region to subtype selectivity varies with each ligand; moreover, while several regions are critical for the pharmacological selectivity of all ligands, others are involved in the selectivity of only some compounds. The selectivity displayed by beta-adrenergic compounds towards beta 1 or beta 2 receptor subtypes thus results from a particular combination of interactions between each ligand and each of the subsites, variably distributed over the seven transmembrane regions of the receptor; these subsites are presumably defined by the individual structural properties of the ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / metabolism
  • Adrenergic beta-Antagonists / metabolism
  • Amino Acid Sequence
  • Animals
  • Escherichia coli / metabolism
  • Ethanolamines / metabolism
  • Imidazoles / metabolism
  • Kinetics
  • Molecular Sequence Data
  • Norepinephrine / metabolism
  • Procaterol
  • Propanolamines
  • Protein Engineering
  • Receptors, Adrenergic, beta / genetics
  • Receptors, Adrenergic, beta / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Structure-Activity Relationship
  • Thermodynamics


  • Adrenergic beta-Agonists
  • Adrenergic beta-Antagonists
  • Ethanolamines
  • Imidazoles
  • Propanolamines
  • Receptors, Adrenergic, beta
  • Recombinant Fusion Proteins
  • ICI 118551
  • CGP 20712A
  • Norepinephrine
  • Procaterol