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Conformational dynamics of a G protein-coupled receptor helix 8 in lipid membranes
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Dijkman, Patricia M., Muñoz-García, Juan C., Steven R., Lavington, Suemy Kumagai, Patricia , dos Reis, Rosana I., Yin, Daniel , Stansfeld, Phillip J., Costa-Filho, Antonio José and Watt , Anthony (2020) Conformational dynamics of a G protein-coupled receptor helix 8 in lipid membranes. Science Advances, 6 (33). eaav8207. doi:10.1126/sciadv.aav8207
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Official URL: https://doi.org/10.1126/sciadv.aav8207
Abstract
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 ß-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.
| Item Type: | Journal Article | ||||||||||||||||||||||||||||||||||||
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| Subjects: | Q Science > QH Natural history > QH426 Genetics R Medicine > RM Therapeutics. Pharmacology |
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| Divisions: | Faculty of Science > Chemistry Faculty of Science > Life Sciences (2010- ) |
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| Library of Congress Subject Headings (LCSH): | G proteins -- Receptors, Drug development -- Research, Human genome, Human gene mapping | ||||||||||||||||||||||||||||||||||||
| Journal or Publication Title: | Science Advances | ||||||||||||||||||||||||||||||||||||
| Publisher: | American Association for the Advancement of Science | ||||||||||||||||||||||||||||||||||||
| ISSN: | 2375-2548 | ||||||||||||||||||||||||||||||||||||
| Official Date: | 2020 | ||||||||||||||||||||||||||||||||||||
| Dates: |
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| Date of first compliant deposit: | 30 July 2020 | ||||||||||||||||||||||||||||||||||||
| Volume: | 6 | ||||||||||||||||||||||||||||||||||||
| Number: | 33 | ||||||||||||||||||||||||||||||||||||
| Article Number: | eaav8207 | ||||||||||||||||||||||||||||||||||||
| DOI: | 10.1126/sciadv.aav8207 | ||||||||||||||||||||||||||||||||||||
| Status: | Peer Reviewed | ||||||||||||||||||||||||||||||||||||
| Publication Status: | Published | ||||||||||||||||||||||||||||||||||||
| Access rights to Published version: | Open Access | ||||||||||||||||||||||||||||||||||||
| Copyright Holders: | Copyright © 2020 The Authors | ||||||||||||||||||||||||||||||||||||
| RIOXX Funder/Project Grant: |
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