Structure‐function studies with G protein‐coupled receptors as a paradigm for improving drug discovery and development of therapeutics

Abstract

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.

Insights into cellular signalling by G protein coupled receptor transactivation of cell surface protein kinase receptors

“…As a consequence, the largest group of therapeutic agents today target GPCRs (McNeely et al 2012). In addition, some of the landmark discoveries in cell biology and receptor signal transduction were derived from studies of GPCR signalling.…”

Recombinant G Protein-Coupled Receptor Expression in Saccharomyces cerevisiae for Protein Characterization

“…Due to the low expression in native systems, the poor quality of heterologous expression, difficult purification, and instability, studying these receptors in vitro is challenging (Allen, Ribeiro, Horuk, & Handel, 2009;Doré et al, 2011;Jones, Greene, Grygon, Doranz, & Brown, 2008;Langelaan, Ngweniform, & Rainey, 2011;McNeely, Naranjo, & Robinson, 2012;Wisedchaisri, Reichow, & Gonen, 2011). The previous purification of functional A 2 aR has shown that in order to retain its α-helical content and ligand-binding activity, the presence of cholesteryl hemisuccinate (CHS) is required when purified in dodecylmaltoside (DDM) (O'Malley et al, 2007).…”

Schilddrüsenhormonwirkung – jenseits klassischer Konzepte

“…Zudem unterliegen Thyronamine selbst einer schnellen Veränderung durch Metabolisierung [28]. Aufgrund ihrer zentralen Rolle für die Signaltransduktion sind die möglichen Thyronamin-Rezeptoren, GPCRs, äußerst interessante Zielmoleküle für eine pharmakologische Intervention [21]. Im Zusammenhang mit Thyronaminen lässt sich die Entwicklung neuer Therapeutika zur Regulation z.B.…”