Agonist induction, conformational selection, and mutant receptors.
Current models of receptor activation are based on either of two basic mechanisms: agonist induction or conformational selection. The importance of one pathway relative to the other is controversial. In this article, the impossibility of distinguishing between the two mechanisms under a thermodynamic approach is shown. The effect of receptor mutation on the constants governing ligand-receptor equilibria is discussed. The two-state model of agonism both in its original formulation (one cycle) and including multiple active states (multiple cycles) is used. Pharmacological equations for the double (two cycles) two-state model are derived. The simulations performed suggest that the double two-state model of agonism can be a useful model for assessing quantitatively the changes in pharmacological activity following receptor mutation.
Giraldo
Jesús
J
Grup de Modelització Estructural i Funcional de Sistemes Biològics, Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain. jesus.giraldo@uab.es
D003198:Computer Simulation; D008024:Ligands; D008956:Models, Chemical; D009154:Mutation; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry* / Q000235:genetics; D015398:Signal Transduction
D008024:Ligands; D043562:Receptors, G-Protein-Coupled