Structure-function studies with G protein-coupled receptors as a paradigm for improving drug discovery and therapeutic development

There are a great variety of human membrane proteins, which currently form the largest group of marketed drug targets. However, despite the advances in drug design, promiscuity between drug molecules and targets often leads to undesired signaling effects, which result in side effects from treatment. In this review, one family of membrane proteins – G protein-coupled receptors (GPCRs) – is used as a model to review experimental techniques that may be used to examine the activity of membrane proteins. As these receptors are highly relevant to healthy human physiology and represent the largest family of drug targets, they represent an excellent model for membrane proteins in general. We also review experimental evidence that suggests there may be multiple ways to target a GPCR – and by extension, membrane proteins – to more effectively target unhealthy phenotypes while reducing the occurrence and severity of side effects.