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Structural insights into positive and negative allosteric regulation of a G protein-coupled receptor through protein-lipid interactions
Bruzzese, Agustín (Universitat Autònoma de Barcelona. Institut de Neurociències)
Gil Giró, Carles (Universitat Autònoma de Barcelona. Institut de Neurociències)
Dalton, James A. R (Universitat Autònoma de Barcelona. Institut de Neurociències)
Giraldo, Jesús (Universitat Autònoma de Barcelona. Institut de Neurociències)

Fecha: 2018
Resumen: Lipids are becoming known as essential allosteric modulators of G protein-coupled receptor (GPCRs). However, how they exert their efects on GPCR conformation at the atomic level is still unclear. In light of recent experimental data, we have performed several long-timescale molecular dynamics (MD) simulations, totalling 24 μs, to rigorously map allosteric modulation and conformational changes in the β2 adrenergic receptor (β2AR) that occur as a result of interactions with three diferent phospholipids. In particular, we identify diferent sequential mechanisms behind receptor activation and deactivation, respectively, mediated by specifc lipid interactions with key receptor regions. We show that net negatively charged lipids stabilize an active-like state of β2AR that is able to dock Gsα protein. Clustering of anionic lipids around the receptor with local distortion of membrane thickness is also apparent. On the other hand, net-neutral zwitterionic lipids inactivate the receptor, generating either fully inactive or intermediate states, with kinetics depending on lipid headgroup charge distribution and hydrophobicity. These chemical diferences alter membrane thickness and density, which diferentially destabilize the β2AR active state through lateral compression efects.
Derechos: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Lengua: Anglès
Documento: article ; recerca ; publishedVersion
Publicado en: Scientific reports (Nature Publishing Group), Vol. 8 (2018) , art. 4456, ISSN 2045-2322

DOI: 10.1038/s41598-018-22735-6
PMID: 29535353


14 p, 7.0 MB

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 Registro creado el 2019-06-18, última modificación el 2021-01-26



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