Title:
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The pathway of ligand entry from the membrane bilayer to a lipid G protein-coupled receptor.
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Author:
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Stanley, Nathaniel H., 1983-; Pardo, Leonardo; De Fabritiis, Gianni
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Abstract:
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The binding process through the membrane bilayer of lipid-like ligands to a protein target is an important but poorly explored recognition process at the atomic level. In this work we succeeded in resolving the binding of the lipid inhibitor ML056 to the sphingosine-1-phosphate receptor 1 (S1P1R) using unbiased molecular dynamics simulations with an aggregate sampling of over 800 μs. The binding pathway is a multi-stage process consisting of the ligand diffusing in the bilayer leaflet to contact a "membrane vestibule" at the top of TM 7, subsequently moving from this lipid-facing vestibule to the orthosteric binding cavity through a channel formed by TMs 1 and 7 and the N-terminal of the receptor. Unfolding of the N-terminal alpha-helix increases the volume of the channel upon ligand entry, helping to reach the crystallographic pose that also corresponds to the predicted favorable pose. The relaxation timescales of the binding process show that the binding of the ligand to the "membrane vestibule" is the rate-limiting step in the multi microseconds timescale. We comment on the significance and parallels of the binding process in the context of other binding studies. |
Abstract:
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The authors would like to thank the volunteers of GPUGRID.net for donating compute time to this project. LP (SAF2013-48271-C2-2-R) and GDF (BIO2014-53095-P) acknowledge support by the Spanish Ministry of Science and Innovation and FEDER. |
Subject(s):
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-Dinàmica molecular -- Simulació per ordinador -Neurotransmissors |
Rights:
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This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
http://creativecommons.org/licenses/by/4.0/ |
Document type:
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Article Article - Published version |
Published by:
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Nature publishing group
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