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  Position of transmembrane Helix 6 determines receptor G protein coupling specificity.

Rose, A. S., Elgeti, M., Zachariae, U., Grubmüller, H., Hofmann, K. P., Scheerer, P., et al. (2014). Position of transmembrane Helix 6 determines receptor G protein coupling specificity. Journal of the American Chemical Society, 136(32), 11244-11247. doi:10.1021/ja5055109.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0023-CE72-E Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-CBD1-9
Genre: Journal Article

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http://pubs.acs.org/doi/pdf/10.1021/ja5055109 (Publisher version)
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 Creators:
Rose, A. S., Author
Elgeti, M., Author
Zachariae, U., Author
Grubmüller, H.1, Author              
Hofmann, K. P., Author
Scheerer, P., Author
Hildebrand, P. W., Author
Affiliations:
1Department of Theoretical and Computational Biophysics, MPI for biophysical chemistry, Max Planck Society, ou_578631              

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 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.

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Language(s): eng - English
 Dates: 2014-07-212014-08-13
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1021/ja5055109
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Title: Journal of the American Chemical Society
Source Genre: Journal
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Pages: - Volume / Issue: 136 (32) Sequence Number: - Start / End Page: 11244 - 11247 Identifier: -