Molecular determinants of GPCR pharmacogenetics: Deconstructing the population variants in β2-adrenergic receptor.

Abstract

G protein-coupled receptors (GPCRs) are membrane proteins that play a central role in cell signaling and constitute one of the largest classes of drug targets. The molecular mechanisms underlying GPCR function have been characterized by several experimental and computational methods and provide an understanding of their role in physiology and disease. Population variants arising from nsSNPs affect the native function of GPCRs and have been implicated in differential drug response. In this chapter, we provide an overview on GPCR structure and activation, with a special focus on the β2-adrenergic receptor (β2-AR). First, we discuss the current understanding of the structural and dynamic features of the wildtype receptor. Subsequently, the population variants identified in this receptor from clinical and large-scale genomic studies are described. We show how computational approaches such as bioinformatics tools and molecular dynamics simulations can be used to characterize the variant receptors in comparison to the wildtype receptor. In particular, we discuss three examples of clinically important variants and discuss how the structure and function of these variants differ from the wildtype receptor at a molecular level. Overall, the chapter provides an overview of structure and function of GPCR variants and is a step towards the study of inter-individual differences and personalized medicine.