Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol

Manna, Moutusi; Niemelä, Miia; Tynkkynen, Joona; Javanainen, Matti; Kulig, Waldemar; Müller, Daniel J.; Róg, Tomasz; Vattulainen, Ilpo

doi:10.7554/elife.18432

Cited by 130 publications

(178 citation statements)

References 68 publications

Supporting

Mentioning

149

Contrasting

Order By: Relevance

“…Molecular dynamics (MD) simulations have provided structural insights into GPCR-lipid interactions. Atomistic simulations identified multiple cholesterol binding sites on the surface of GPCRs, the occupancy of which resulted in increased conformational stability (Guixa-Gonzalez et al, 2017;Lyman et al, 2009;Manna et al, 2016). Frequent insertion of PG into the opening between TM6 and TM7 was observed in atomistic simulations of b2 adrenergic receptor in the active state conformation, suggesting a possible explanation for the influence of anionic lipids on GPCR activation (Neale et al, 2015).…”

Section: Introductionmentioning

confidence: 94%

State-dependent Lipid Interactions with the A2a Receptor Revealed by MD Simulations Using In Vivo-Mimetic Membranes

et al. 2019

View full text Add to dashboard Cite

Graphical Abstract Highlights d MD simulations show state-dependent binding of lipids to the Adenosine A2a receptor d Nine lipid interaction sites were revealed, for GM3, cholesterol and PIP 2 d Binding of PIP 2 enhanced the association of mini-Gs with the A2a receptor d These results indicate lipids may allosterically regulate GPCRs SUMMARY Membranes are known to have modulatory effects on G protein-coupled receptors (GPCRs) via specific lipid interactions. However, the mechanisms of such modulations in physiological conditions and how they influence GPCR functions remain unclear.Here we report coarse-grained molecular dynamics simulations on the Adenosine A2a receptor in different conformational states embedded in an in vivo-mimetic membrane model. Nine lipid interaction sites were revealed. The strength of lipid interactions with these sites showed a degree of dependence on the conformational states of the receptor, suggesting that these lipids may regulate the conformational dynamics of the receptor. In particular, we revealed a dual role of PIP 2 on A2aR activation that involves both stabilization of the characteristic outward tilt of TM6 and enhancement of A2aR-mini-Gs association. Our results demonstrated that the bound lipids allosterically regulate the functional properties of GPCRs. These protein-lipid interactions provide a springboard for design of allosteric modulators of GPCRs. which are governed by both the protein receptor and its bound lipids. This opens up new prospects for the pharmacology of GPCRs as their druggable space is expanded to include the bound lipids. The sensitivity of protein-lipid interactions toward the receptor conformational state and the lipid environment may thus provide a platform for designing subtype-selective and cell type-selective drugs. STAR+METHODSDetailed methods are provided in the online version of this paper and include the following:

show abstract

Section: Introductionmentioning

confidence: 94%

State-dependent Lipid Interactions with the A2a Receptor Revealed by MD Simulations Using In Vivo-Mimetic Membranes

et al. 2019

View full text Add to dashboard Cite

show abstract

“…GPCRs constitute one of the largest classes of membrane proteins, and their key roles in many biological processes mean that they make up approximately one-third of all drug targets [58]. Many GPCRs have been shown to bind [59,60] and have been suggested to be functionally modulated by cholesterol [61][62][63]. These include the intensively studied adenosine 2A (A 2A R) and β2-adrenergic (β-2AR) receptors.…”

Section: Binding Of Cholesterol To Gpcrs and Other Membrane Proteinsmentioning

confidence: 99%

The energetics of protein–lipid interactions as viewed by molecular simulations

Corey

Stansfeld

Sansom

2019

Biochemical Society Transactions

View full text Add to dashboard Cite

Membranes are formed from a bilayer containing diverse lipid species with which membrane proteins interact. Integral, membrane proteins are embedded in this bilayer, where they interact with lipids from their surroundings, whilst peripheral membrane proteins bind to lipids at the surface of membranes. Lipid interactions can influence the function of membrane proteins, either directly or allosterically. Both experimental (structural) and computational approaches can reveal lipid binding sites on membrane proteins. It is, therefore, important to understand the free energies of these interactions. This affords a more complete view of the engagement of a particular protein with the biological membrane surrounding it. Here, we describe many computational approaches currently in use for this purpose, including recent advances using both free energy and unbiased simulation methods. In particular, we focus on interactions of integral membrane proteins with cholesterol, and with anionic lipids such as phosphatidylinositol 4,5-bis-phosphate and cardiolipin. Peripheral membrane proteins are exemplified via interactions of PH domains with phosphoinositide-containing membranes. We summarise the current state of the field and provide an outlook on likely future directions of investigation.

show abstract

“…For example, a crystal structure of the Class A GPCR β2-adrenegic receptor identified cholesterol bound to the intracellular region of TM4 (23), which was validated by observation of cholesterol binding to the same binding site in MD simulations (24). MD simulations have shown how cholesterol binding can modulate the conformation dynamics of the β2 adrenergic receptor (25). MD simulations have also demonstrated that phosphatidylinositol (4,5)-bisphosphate (PIP2) binds more favourably to active than to inactive states of the adenosine 2A receptor thus favouring receptor activation (26).…”

Section: Introductionmentioning

confidence: 88%

The Glycosphingolipid GM3 Modulates Conformational Dynamics of the Glucagon Receptor

Ansell

Song

Sansom

2020

Preprint

View full text Add to dashboard Cite

The extracellular domain (ECD) of Class B1 G-protein coupled receptors (GPCRs) plays a central role in signal transduction and is uniquely positioned to sense both the extracellular and membrane environments. Whilst recent studies suggest a role for membrane lipids in the modulation of Class A and Class F GPCR signalling properties, little is known about the effect of lipids on Class B1 receptors. In this study, we employed multiscale molecular dynamics (MD) simulations to access the dynamics of the glucagon receptor (GCGR) ECD in the presence of native-like membrane bilayers.Simulations showed that the ECD could move about a hinge region formed by residues Q122-E126 to adopt both closed and open conformations relative to the TMD. ECD movements were modulated by binding of the glycosphingolipid GM3. These large-scale fluctuations in ECD conformation that may affect the ligand binding and receptor activation properties. We also identify a unique PIP2 interaction profile near ICL2/TM3 at the G-protein coupling interface, suggesting a mechanism of engaging G-proteins which may have a distinct dependence on PIP2 compared to Class A GPCRs.Given the structural conservation of Class B1 GPCRs, the modulatory effects of GM3 and PIP2 on GCGR may be conserved across these receptors, offering new insights into potential therapeutic targeting. Statement of SignificanceThe role of lipids in regulation of Class B GPCRs remains elusive, despite recent structural advances. In this study, multi-scale molecular dynamics simulations are used to evaluate lipid interactions with the glucagon receptor, a Class B1 GPCR. We find that the glycosphingolipid GM3 binds to the glucagon receptor extracellular domain (ECD), modulating the dynamics of the ECD and promoting movement away from the transmembrane domain . We also identify a unique PIP2 interaction fingerprint in a region known to be important for bridging G-protein coupling in Class A GPCRs. Thus, this study provides molecular insight into the behaviour of the glucagon receptor in a complex lipid bilayer environment which may aid understanding of glucagon receptor signalling properties.GCGR_main text v16 figs MS biorxiv.docx

show abstract

Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol

Cited by 130 publications

References 68 publications

State-dependent Lipid Interactions with the A2a Receptor Revealed by MD Simulations Using In Vivo-Mimetic Membranes

State-dependent Lipid Interactions with the A2a Receptor Revealed by MD Simulations Using In Vivo-Mimetic Membranes

The energetics of protein–lipid interactions as viewed by molecular simulations

The Glycosphingolipid GM3 Modulates Conformational Dynamics of the Glucagon Receptor

Contact Info

Product

Resources

About