There are 475 marketed drugs (~34% of all FDA-approved therapeutic agent agents) targeting 108 members of the GPCR superfamily ( Hauser et al., 2018 Hauser et al., 2017 Allen and Roth, 2011). Therefore, GPCRs are important drug targets. IntroductionĪs the largest and most diverse group of membrane receptors in eukaryotes, GPCRs mediate a wide variety of physiological functions ( Lagerström and Schiöth, 2008 Rosenbaum et al., 2009 Katritch et al., 2012 Venkatakrishnan et al., 2013 Katritch et al., 2013), including vision, olfaction, taste, neurotransmission, endocrine and immune responses via more than 800 family members, and are involved in many diseases ( Rana et al., 2001 Smit et al., 2007 Vassart and Costagliola, 2011 Thompson et al., 2014 Hauser et al., 2018). Such an architecture might have facilitated GPCRs to emerge as a highly successful family of proteins for signal transduction in nature. As a module responsible for activation, the common pathway allows for decoupling of the evolution of the ligand binding site and G-protein-binding region. The common activation pathway provides the mechanistic interpretation of constitutively activating, inactivating and disease mutations. Site-directed mutagenesis experiments support this proposition and reveal that rational mutations of residues in this pathway can be used to obtain receptors that are constitutively active or inactive.

The pathway unifies previous findings into a common activation mechanism and strings together the scattered key motifs such as CWxP, DRY, Na + pocket, NPxxY and PIF, thereby directly linking the bottom of ligand-binding pocket with G-protein coupling region. By analyzing the conformational changes in 234 structures from 45 class A GPCRs, we discovered a common GPCR activation pathway comprising of 34 residue pairs and 35 residues. Here, we report a framework to quantify conformational changes. However, what leads to TM6 movement and the key residue level changes of this movement remain less well understood. GPCR activation is an allosteric process that couples agonist binding to G-protein recruitment, with the hallmark outward movement of transmembrane helix 6 (TM6). Understanding receptor activation mechanism is critical for discovering novel therapeutics since about one-third of all marketed drugs target members of this family. Class A G-protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology.

Key ionic activation bypass