TY - JOUR
T1 - Position of transmembrane helix 6 determines receptor G protein coupling specificity
AU - Rose, Alexander S.
AU - Elgeti, Matthias
AU - Zachariae, Ulrich
AU - Grubmüller, Helmut
AU - Hofmann, Klaus P.
AU - Scheerer, Patrick
AU - Hildebrand, Peter W.
PY - 2014/8/13
Y1 - 2014/8/13
N2 - G protein coupled receptors (GPCRs) transmit extracellular signals into the cell by binding and activating different intracellular signaling proteins, such as G proteins (Gaβγ, 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 ß- adrenoceptor (ß2AR) in complex with C-terminal peptides derived from the key interaction site of Ga (GaCT) as surrogate of Gaßγ. We find that GiaCT and GsaCT exploit distinct cytoplasmic receptor conformations that coexist in the uncomplexed ß2AR. The slim GiaCT stabilizes a ß2AR* conformation, not accessible to the bulkier GsaCT, which requires a larger TM6 outward tilt for binding. Our results suggest that the TM6 conformational heterogeneity regulates the catalytic activity of ß2AR* toward Gi or Gs.
AB - G protein coupled receptors (GPCRs) transmit extracellular signals into the cell by binding and activating different intracellular signaling proteins, such as G proteins (Gaβγ, 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 ß- adrenoceptor (ß2AR) in complex with C-terminal peptides derived from the key interaction site of Ga (GaCT) as surrogate of Gaßγ. We find that GiaCT and GsaCT exploit distinct cytoplasmic receptor conformations that coexist in the uncomplexed ß2AR. The slim GiaCT stabilizes a ß2AR* conformation, not accessible to the bulkier GsaCT, which requires a larger TM6 outward tilt for binding. Our results suggest that the TM6 conformational heterogeneity regulates the catalytic activity of ß2AR* toward Gi or Gs.
UR - http://www.scopus.com/inward/record.url?scp=84906088654&partnerID=8YFLogxK
U2 - 10.1021/ja5055109
DO - 10.1021/ja5055109
M3 - Article
C2 - 25046433
AN - SCOPUS:84906088654
VL - 136
SP - 11244
EP - 11247
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 32
ER -