Receptors' Mosaics and Allostery for Pharmacology

Abstract

Understanding how receptors respond to stimuli in the brain is a tremendous challenge with relevant implications for human health.Over the last few years, receptors have been shown to function as both monomers and heteromers, i.e. macromolecular complexes composed of at least two different functional receptor units, displaying biochemical properties that are demonstrably different from those of their individual components. These are the so-called “receptor mosaics” (RM; dimeric or high-order receptor oligomers). The cooperative interactions established in the RMs due to both exogenous ligand binding and allosteric mechanisms at the receptor/receptor interface alter the pharmacology response of the single receptor. For instance, RMs markedly expand the diversity and specificity of G protein-coupled receptors (GPCR) signaling, particularly in neural cells. Thus, the pharmacology of the binding pockets of the different receptors building up the RM can be substantially distinct with respect their pharmacology in the respective monomer.We have developed computational approaches to characterize allosteric effects on membrane proteins (Maggi et al., J Phys Chem Lett. 2018; Cao et al. Molecules, 2018; Cao et al. PlosOne, 2015) including membrane-dependent regulation processes, dimerization models (Zeng et al., Int. J. Mol. Sci., 2018), as well as self-assembly protocol (paper in preparation) to establish the most stable oligomer given a set of membrane proteins. Next, we have exploited this for in silico pharmacological approaches.