Position of Transmembrane Helix 6 Determines Receptor G Protein Coupling Specificity

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• 作者：Alexander S. Rose ; Matthias Elgeti ; Ulrich Zachariae ; Helmut Grubm眉ller ; Klaus Peter Hofmann ; Patrick Scheerer ; Peter W. Hildebrand
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：August 13, 2014
• 年：2014
• 卷：136
• 期：32
• 页码：11244-11247
• 全文大小：322K
• ISSN：1520-5126

文摘

G protein coupled receptors (GPCRs) transmit extracellular signals into the cell by binding and activating different intracellular signaling proteins, such as G proteins (G伪尾纬, families Gi, Gs, Gq, G_12/13) or arrestins. To address the issue of Gs vs Gi coupling specificity, we carried out molecular dynamics simulations of lipid-embedded active 尾₂-adrenoceptor (尾₂AR*) in complex with C-terminal peptides derived from the key interaction site of G伪 (G伪CT) as surrogate of G伪尾纬. We find that Gi伪CT and Gs伪CT exploit distinct cytoplasmic receptor conformations that coexist in the uncomplexed 尾₂AR*. The slim Gi伪CT stabilizes a 尾₂AR* conformation, not accessible to the bulkier Gs伪CT, which requires a larger TM6 outward tilt for binding. Our results suggest that the TM6 conformational heterogeneity regulates the catalytic activity of 尾₂AR* toward Gi or Gs.