Efficiency measures the conversion of agonist binding energy into receptor conformational change.

ABSTRACT: Receptors alternate between resting?active conformations that bind agonists with low?high affinity. Here, we define a new agonist attribute, energy efficiency (?), as the fraction of ligand-binding energy converted into the mechanical work of the activation conformational change. ? depends only on the resting/active agonist-binding energy ratio. In a plot of activation energy versus binding energy (an "efficiency" plot), the slope gives ? and the y intercept gives the receptor's intrinsic activation energy (without agonists; ?G0). We used single-channel electrophysiology to estimate ? for eight different agonists and ?G0 in human endplate acetylcholine receptors (AChRs). From published equilibrium constants, we also estimated ? for agonists of KCa1.1 (BK channels) and muscarinic, ?-aminobutyric acid, glutamate, glycine, and aryl-hydrocarbon receptors, and ?G0 for all of these except KCa1.1. Regarding AChRs, ? is 48-56% for agonists related structurally to acetylcholine but is only ?39% for agonists related to epibatidine; ?G0 is 8.4 kcal/mol in adult and 9.6 kcal/mol in fetal receptors. Efficiency plots for all of the above receptors are approximately linear, with ? values between 12% and 57% and ?G0 values between 2 and 12 kcal/mol. Efficiency appears to be a general attribute of agonist action at receptor binding sites that is useful for understanding binding mechanisms, categorizing agonists, and estimating concentration-response relationships.

SUBMITTER: Nayak TK 

PROVIDER: S-EPMC6445574 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature