title: Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region.
abstract: Class A G-protein-coupled receptors (GPCRs) are a large family of membrane proteins that mediate a wide variety of physiological functions, including vision, neurotransmission and immune responses. They are the targets of nearly one-third of all prescribed medicinal drugs such as beta blockers and antipsychotics. GPCR activation is facilitated by extracellular ligands and leads to the recruitment of intracellular G proteins. Structural rearrangements of residue contacts in the transmembrane domain serve as 'activation pathways' that connect the ligand-binding pocket to the G-protein-coupling region within the receptor. In order to investigate the similarities in activation pathways across class A GPCRs, we analysed 27 GPCRs from diverse subgroups for which structures of active, inactive or both states were available. Here we show that, despite the diversity in activation pathways between receptors, the pathways converge near the G-protein-coupling region. This convergence is mediated by a highly conserved structural rearrangement of residue contacts between transmembrane helices 3, 6 and 7 that releases G-protein-contacting residues. The convergence of activation pathways may explain how the activation steps initiated by diverse ligands enable GPCRs to bind a common repertoire of G proteins.
authors.forename: A J
authors.initials: AJ
authors.lastname: Venkatakrishnan
authors.forename: Xavier
authors.initials: X
authors.lastname: Deupi
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lebon
authors.forename: Franziska M
authors.initials: FM
authors.lastname: Heydenreich
authors.forename: Tilman
authors.initials: T
authors.lastname: Flock
authors.forename: Tamara
authors.initials: T
authors.lastname: Miljus
authors.forename: Santhanam
authors.initials: S
authors.lastname: Balaji
authors.forename: Michel
authors.initials: M
authors.lastname: Bouvier
authors.forename: Dmitry B
authors.initials: DB
authors.lastname: Veprintsev
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Tate
authors.forename: Gebhard F X
authors.initials: GF
authors.lastname: Schertler
authors.forename: M Madan
authors.initials: MM
authors.lastname: Babu
mesh_terms: D001665:Binding Sites; D017124:Conserved Sequence; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D017483:Receptors, Vasopressin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D040681:Structural Homology, Protein
chemical_list: C585768:AVPR2 protein, human; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D017483:Receptors, Vasopressin; D020962:Heterotrimeric GTP-Binding Proteins