Abstract

G-protein coupled receptors (GPCRs) comprise the largest family of proteins in our body, which have many important physiological functions and are implicated in the pathophysiology of many serious diseases. GPCRs therefore are significant targets in pharmaceutical research. GPCRs share the common architecture of seven plasma membrane-spanning segments connected to each other with three extracellular and three intracellular loops. In addition, GPCRs contain an extracellular N-terminal region and an intracellular C-terminal tail. GPCRs could stimulate different intracellular G-proteins (internal stimuli) and signaling pathways after their interaction with different ligands (external stimuli). The exceptional functional plasticity of GPCRs could be attributed to their inherent dynamic nature to adopt different active conformations, which are stabilized differentially by different stimuli as well as by several mutations. This review describes the structural changes of GPCRs associated with their activation. Understanding the dynamic nature of GPCRs could potentially contribute in the development of future structure-based approaches to design new receptor-specific, signaling-selective ligands, which will enrich the pharmaceutical armamentarium against various diseases

Keywords: GPCRs, (inverse)agonists, binding site crevice, membrane-spanning segments, structure, conformational changes, G-proteins, signaling, functional plasticity, mutations