title: Position of transmembrane helix 6 determines receptor G protein coupling specificity.
abstract: G protein coupled receptors (GPCRs) transmit extracellular signals into the cell by binding and activating different intracellular signaling proteins, such as G proteins (Gαβγ, families Gi, Gs, Gq, G12/13) or arrestins. To address the issue of Gs vs Gi coupling specificity, we carried out molecular dynamics simulations of lipid-embedded active β2-adrenoceptor (β2AR*) in complex with C-terminal peptides derived from the key interaction site of Gα (GαCT) as surrogate of Gαβγ. We find that GiαCT and GsαCT exploit distinct cytoplasmic receptor conformations that coexist in the uncomplexed β2AR*. The slim GiαCT stabilizes a β2AR* conformation, not accessible to the bulkier GsαCT, which requires a larger TM6 outward tilt for binding. Our results suggest that the TM6 conformational heterogeneity regulates the catalytic activity of β2AR* toward Gi or Gs.
authors.affiliation: Institut für Medizinische Physik und Biophysik, ‡AG ProteiInformatics, and #AG Protein X-ray Crystallography, Charité-Universitätsmedizin Berlin , Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Rose
authors.forename: Matthias
authors.initials: M
authors.lastname: Elgeti
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zachariae
authors.forename: Helmut
authors.initials: H
authors.lastname: Grubmüller
authors.forename: Klaus Peter
authors.initials: KP
authors.lastname: Hofmann
authors.forename: Patrick
authors.initials: P
authors.lastname: Scheerer
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hildebrand
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D003198:Computer Simulation; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry*; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*; D012243:Rhodopsin / Q000737:chemistry; D015398:Signal Transduction
chemical_list: D010455:Peptides; D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; D012243:Rhodopsin