G-Protein-Coupled Receptor-Membrane Interactions Depend on the Receptor Activation State
© 2019 Wiley Periodicals, Inc.
| Veröffentlicht in: | Journal of computational chemistry. - 1984. - 41(2020), 5 vom: 15. Feb., Seite 460-471 |
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| Format: | Online-Aufsatz |
| Sprache: | English |
| Veröffentlicht: |
2020
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| Zugriff auf das übergeordnete Werk: | Journal of computational chemistry |
| Schlagworte: | Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. G-protein-coupled receptors Gaussian accelerated molecular dynamics adenosine A1 receptor enhanced sampling protein-lipid interactions Lipid Bilayers mehr... |
| Zusammenfassung: | © 2019 Wiley Periodicals, Inc. G-protein-coupled receptors (GPCRs) are the largest family of human membrane proteins and serve as primary targets of approximately one-third of currently marketed drugs. In particular, adenosine A1 receptor (A1 AR) is an important therapeutic target for treating cardiac ischemia-reperfusion injuries, neuropathic pain, and renal diseases. As a prototypical GPCR, the A1 AR is located within a phospholipid membrane bilayer and transmits cellular signals by changing between different conformational states. It is important to elucidate the lipid-protein interactions in order to understand the functional mechanism of GPCRs. Here, all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method were performed on both the inactive (antagonist bound) and active (agonist and G-protein bound) A1 AR, which was embedded in a 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) lipid bilayer. In the GaMD simulations, the membrane lipids played a key role in stabilizing different conformational states of the A1 AR. Our simulations further identified important regions of the receptor that interacted distinctly with the lipids in highly correlated manner. Activation of the A1 AR led to differential dynamics in the upper and lower leaflets of the lipid bilayer. In summary, GaMD enhanced simulations have revealed strongly coupled dynamics of the GPCR and lipids that depend on the receptor activation state. © 2019 Wiley Periodicals, Inc |
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| Beschreibung: | Date Completed 29.06.2021 Date Revised 13.11.2023 published: Print-Electronic Citation Status MEDLINE |
| ISSN: | 1096-987X |
| DOI: | 10.1002/jcc.26082 |