Skip to main content

A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model.

Publication ,  Journal Article
Samama, P; Cotecchia, S; Costa, T; Lefkowitz, RJ
Published in: J Biol Chem
March 5, 1993

We have replaced the C-terminal portion of the third intracellular loop of the beta 2-adrenergic receptor (residues 266-272) with the homologous region of the alpha 1B-adrenergic receptor. In a fashion analogous to the reciprocal mutations of the alpha 1B receptor previously described (Cotecchia, S., Exum, S., Caron, M. G., and Lefkowitz, R. J. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 2896-2900), this conservative substitution leads to agonist-independent activation of adenylyl cyclase. In addition, the constitutively active mutant receptor exhibits: (i) an increased affinity for agonists (even in the absence of guanine nucleotide-binding regulatory protein (G protein)) but not antagonists, with the extent of affinity increase being correlated with the intrinsic activity of the ligand; (ii) an increased potency of agonists for stimulation of adenylyl cyclase; and (iii) an increased intrinsic activity of partial agonists. We document that our experimental findings with the mutant receptor cannot be adequately rationalized within the theoretical framework of the Ternary Complex Model (De Lean, A., Stadel, J. M., and Lefkowitz, R. J. (1980) J. Biol. Chem. 255, 7108-7117) which postulates that receptor activation requires the agonist-promoted formation of an active, "ternary" complex of agonist, receptor, and G protein. We show, through extensive computer simulations, that an extended version of this model that includes an explicit isomerization of the receptor (R) to an active state (R*) closely models all our findings for both the mutant and the wild-type receptors. Study of such constitutively active mutant G protein-coupled receptors should help elucidate the molecular nature of the processes involved in receptor activation.

Duke Scholars

Published In

J Biol Chem

ISSN

0021-9258

Publication Date

March 5, 1993

Volume

268

Issue

7

Start / End Page

4625 / 4636

Location

United States

Related Subject Headings

  • Substrate Specificity
  • Receptors, Adrenergic, beta
  • Protein Conformation
  • Mutagenesis
  • Molecular Sequence Data
  • Models, Chemical
  • GTP-Binding Proteins
  • Enzyme Activation
  • Cricetinae
  • Cell Line
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Samama, P., Cotecchia, S., Costa, T., & Lefkowitz, R. J. (1993). A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model. J Biol Chem, 268(7), 4625–4636.
Samama, P., S. Cotecchia, T. Costa, and R. J. Lefkowitz. “A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model.J Biol Chem 268, no. 7 (March 5, 1993): 4625–36.
Samama P, Cotecchia S, Costa T, Lefkowitz RJ. A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model. J Biol Chem. 1993 Mar 5;268(7):4625–36.
Samama, P., et al. “A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model.J Biol Chem, vol. 268, no. 7, Mar. 1993, pp. 4625–36.
Samama P, Cotecchia S, Costa T, Lefkowitz RJ. A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model. J Biol Chem. 1993 Mar 5;268(7):4625–4636.

Published In

J Biol Chem

ISSN

0021-9258

Publication Date

March 5, 1993

Volume

268

Issue

7

Start / End Page

4625 / 4636

Location

United States

Related Subject Headings

  • Substrate Specificity
  • Receptors, Adrenergic, beta
  • Protein Conformation
  • Mutagenesis
  • Molecular Sequence Data
  • Models, Chemical
  • GTP-Binding Proteins
  • Enzyme Activation
  • Cricetinae
  • Cell Line