title: Understanding the common themes and diverse roles of the second extracellular loop (ECL2) of the GPCR super-family.
abstract: The extracellular loops (ECLs) of G protein-coupled receptors (GPCRs) can bind directly to docked orthosteric or allosteric ligands, they can contain transient contact points for ligand entry into the transmembrane (TM) bundle and they can regulate the activation of the receptor signalling pathways. Of the three ECLs, ECL2 is the largest and most structurally diverse reflecting its functional importance. This has been shown through biochemical techniques and has been supported by the many subsequent crystal structures of GPCRs bound to both agonists and antagonists. ECL2 shares common structural features between (and sometimes across) receptor sub-families and can facilitate ligand entry to the TM core or act directly as a surface of the ligand-binding pocket. Structural similarities seem to underpin common binding mechanisms; however, where these exist, variations in primary sequence ensure ligand-binding specificity. This review will compare current understanding of the structural themes and main functional roles of ECL2 in ligand binding, activation and regulation of the major families of GPCRs.
authors.affiliation: Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Woolley
authors.affiliation: Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK. Electronic address: a.c.conner@bham.ac.uk.
authors.forename: Alex C
authors.initials: AC
authors.lastname: Conner
mesh_terms: D000818:Animals; D006801:Humans; D008958:Models, Molecular; D005810:Multigene Family; D017433:Protein Structure, Secondary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D043562:Receptors, G-Protein-Coupled
keywords: Extracellular loop; Family B; GPCR; Ligand-binding; Receptor activation; Signalling