期刊
SCIENCE ADVANCES
卷 6, 期 33, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aav8207
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资金
- Medical Research Council [G0900076, MR/S009213/1]
- Biotechnology and Biological Sciences Research Council [BB/P01948X/1, BB/R002517/1, BB/S003339/1]
- Wellcome [208361/Z/17/Z]
- UCB Celltech
- FAPESP [2010/17662-8, 2011/21767-2, 2012/20358-4]
- CNPq
- BBSRC [BB/P01948X/2, BB/R002517/1, BB/S003339/1, BB/P01948X/1] Funding Source: UKRI
- EPSRC [EP/R029407/1] Funding Source: UKRI
- MRC [MR/S009213/1, G0900076] Funding Source: UKRI
G protein-coupled receptors (GPCRs) are the largest and pharmaceutically most important class of membrane proteins encoded in the human genome, characterized by a seven-transmembrane helix architecture and a C-terminal amphipathic helix 8 (H8). In a minority of GPCR structures solved to date, H8 either is absent or adopts an unusual conformation. The controversial existence of H8 of the class A GPCR neurotensin receptor 1 (NTS1) has been examined here for the nonthermostabilized receptor in a functionally supporting membrane environment using electron paramagnetic resonance, molecular dynamics simulations, and circular dichroism. Lipid-protein interactions with phosphatidylserine and phosphatidylethanolamine lipids, in particular, stabilize the residues 374 to 390 of NTS1 into forming a helix. Furthermore, introduction of a helix-breaking proline residue in H8 elicited an increase in beta-arrestin-NTS1 interactions observed in pull-down assays, suggesting that the structure and/or dynamics of H8 might play an important role in GPCR signaling.
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