Journal Article

Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region

Venkatakrishnan, A. J., Bouvier, Michel, Babu, M. Madan, Flock, Tilman, Heydenreich, Franziska M., Veprintsev, Dmitry B., Deupi, Xavier, Balaji, Santhanam, Schertler, Gebhard F. X., Miljus, Tamara, Tate, Christopher G., Lebon, Guillaume

2016

Overview

A highly conserved rearrangement of residue contacts functions as a common step in the activation pathways of diverse G-protein-coupled receptors. Structural convergence in GPCRs A comprehensive structural analysis of 27 class A G-protein-coupled receptors (GPCRs) reveals that, despite the extensive diversity in the activation pathways between receptors, the pathways converge near the G-protein-coupling region. The convergence is mediated by a highly conserved structural rearrangement of residue contacts between transmembrane helices. These findings may explain how the activation steps initiated by diverse ligands enable GPCRs to bind a common repertoire of G proteins, and will have implications for the modelling and engineering of GPCRs for structure-based drug discovery. 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 1 , 2 , 3 , 4 . They are the targets of nearly one-third of all prescribed medicinal drugs 5 such as beta blockers and antipsychotics. GPCR activation is facilitated by extracellular ligands and leads to the recruitment of intracellular G proteins 3 , 6 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/114 / 631/92/612/194 / Binding Sites / Biochemistry, Molecular Biology / Cellular signal transduction / Conserved Sequence / Heterotrimeric GTP-Binding Proteins - metabolism / Humanities and Social Sciences / Humans / letter / Life Sciences / Ligands / Membrane proteins / Membranes / Models, Molecular / Molecular biology / multidisciplinary / Mutation / Physiological aspects / Physiology / Protein research / Protein Structure, Secondary / Proteins / Quantitative Methods / Receptors, G-Protein-Coupled - chemistry / Receptors, G-Protein-Coupled - classification / Receptors, G-Protein-Coupled - genetics / Receptors, G-Protein-Coupled - metabolism / Receptors, Vasopressin - chemistry / Receptors, Vasopressin - genetics / Receptors, Vasopressin - metabolism / Science / Signal Transduction / Structural Biology / Structural Homology, Protein / Studies