Lipid Modulation of a Class B GPCR: Elucidating the Modulatory Role of PI(4,5)P2 Lipids

Lisbeth R. Kjølbye; Lars Sørensen; Jun Yan; Nils A. Berglund; Jesper Ferkinghoff-Borg; Carol V. Robinson; Birgit Schiøtt

doi:10.1021/acs.jcim.2c00635

Lipid Modulation of a Class B GPCR: Elucidating the Modulatory Role of PI(4,5)P₂ Lipids

Lisbeth R. Kjølbye, Lars Sørensen, Jun Yan, Nils A. Berglund, Jesper Ferkinghoff-Borg, Carol V. Robinson, Birgit Schiøtt^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

11 Citations (Scopus)

Abstract

Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) lipids have been shown to stabilize an active conformation of class A G-protein coupled receptors (GPCRs) through a conserved binding site, not present in class B GPCRs. For class B GPCRs, previous molecular dynamics (MD) simulation studies have shown PI(4,5)P2 interacting with the Glucagon receptor (GCGR), which constitutes an important target for diabetes and obesity therapeutics. In this work, we applied MD simulations supported by native mass spectrometry (nMS) to study lipid interactions with GCGR. We demonstrate how tail composition plays a role in modulating the binding of PI(4,5)P2 lipids to GCGR. Specifically, we find the PI(4,5)P2 lipids to have a higher affinity toward the inactive conformation of GCGR. Interestingly, we find that in contrast to class A GPCRs, PI(4,5)P2 appear to stabilize the inactive conformation of GCGR through a binding site conserved across class B GPCRs but absent in class A GPCRs. This suggests differences in the regulatory function of PI(4,5)P2 between class A and class B GPCRs.

Original language	English
Journal	Journal of Chemical Information and Modeling
Volume	62
Issue	24
Pages (from-to)	6788-6802
Number of pages	15
ISSN	1549-9596
DOIs	https://doi.org/10.1021/acs.jcim.2c00635
Publication status	Published - Dec 2022

Keywords

Binding Sites
Lipids/chemistry
Molecular Conformation
Molecular Dynamics Simulation
Receptors, G-Protein-Coupled/chemistry

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10.1021/acs.jcim.2c00635

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title = "Lipid Modulation of a Class B GPCR: Elucidating the Modulatory Role of PI(4,5)P2 Lipids",

abstract = "Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) lipids have been shown to stabilize an active conformation of class A G-protein coupled receptors (GPCRs) through a conserved binding site, not present in class B GPCRs. For class B GPCRs, previous molecular dynamics (MD) simulation studies have shown PI(4,5)P2 interacting with the Glucagon receptor (GCGR), which constitutes an important target for diabetes and obesity therapeutics. In this work, we applied MD simulations supported by native mass spectrometry (nMS) to study lipid interactions with GCGR. We demonstrate how tail composition plays a role in modulating the binding of PI(4,5)P2 lipids to GCGR. Specifically, we find the PI(4,5)P2 lipids to have a higher affinity toward the inactive conformation of GCGR. Interestingly, we find that in contrast to class A GPCRs, PI(4,5)P2 appear to stabilize the inactive conformation of GCGR through a binding site conserved across class B GPCRs but absent in class A GPCRs. This suggests differences in the regulatory function of PI(4,5)P2 between class A and class B GPCRs.",

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author = "Kj{\o}lbye, {Lisbeth R.} and Lars S{\o}rensen and Jun Yan and Berglund, {Nils A.} and Jesper Ferkinghoff-Borg and Robinson, {Carol V.} and Birgit Schi{\o}tt",

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year = "2022",

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doi = "10.1021/acs.jcim.2c00635",

language = "English",

volume = "62",

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Lipid Modulation of a Class B GPCR: Elucidating the Modulatory Role of PI(4,5)P₂ Lipids. / Kjølbye, Lisbeth R.; Sørensen, Lars; Yan, Jun et al.
In: Journal of Chemical Information and Modeling, Vol. 62, No. 24, 12.2022, p. 6788-6802.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Lipid Modulation of a Class B GPCR

T2 - Elucidating the Modulatory Role of PI(4,5)P2 Lipids

AU - Kjølbye, Lisbeth R.

AU - Sørensen, Lars

AU - Yan, Jun

AU - Berglund, Nils A.

AU - Ferkinghoff-Borg, Jesper

AU - Robinson, Carol V.

AU - Schiøtt, Birgit

PY - 2022/12

Y1 - 2022/12

N2 - Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) lipids have been shown to stabilize an active conformation of class A G-protein coupled receptors (GPCRs) through a conserved binding site, not present in class B GPCRs. For class B GPCRs, previous molecular dynamics (MD) simulation studies have shown PI(4,5)P2 interacting with the Glucagon receptor (GCGR), which constitutes an important target for diabetes and obesity therapeutics. In this work, we applied MD simulations supported by native mass spectrometry (nMS) to study lipid interactions with GCGR. We demonstrate how tail composition plays a role in modulating the binding of PI(4,5)P2 lipids to GCGR. Specifically, we find the PI(4,5)P2 lipids to have a higher affinity toward the inactive conformation of GCGR. Interestingly, we find that in contrast to class A GPCRs, PI(4,5)P2 appear to stabilize the inactive conformation of GCGR through a binding site conserved across class B GPCRs but absent in class A GPCRs. This suggests differences in the regulatory function of PI(4,5)P2 between class A and class B GPCRs.

AB - Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) lipids have been shown to stabilize an active conformation of class A G-protein coupled receptors (GPCRs) through a conserved binding site, not present in class B GPCRs. For class B GPCRs, previous molecular dynamics (MD) simulation studies have shown PI(4,5)P2 interacting with the Glucagon receptor (GCGR), which constitutes an important target for diabetes and obesity therapeutics. In this work, we applied MD simulations supported by native mass spectrometry (nMS) to study lipid interactions with GCGR. We demonstrate how tail composition plays a role in modulating the binding of PI(4,5)P2 lipids to GCGR. Specifically, we find the PI(4,5)P2 lipids to have a higher affinity toward the inactive conformation of GCGR. Interestingly, we find that in contrast to class A GPCRs, PI(4,5)P2 appear to stabilize the inactive conformation of GCGR through a binding site conserved across class B GPCRs but absent in class A GPCRs. This suggests differences in the regulatory function of PI(4,5)P2 between class A and class B GPCRs.

KW - Binding Sites

KW - Lipids/chemistry

KW - Molecular Conformation

KW - Molecular Dynamics Simulation

KW - Receptors, G-Protein-Coupled/chemistry

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DO - 10.1021/acs.jcim.2c00635

M3 - Journal article

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AN - SCOPUS:85137302397

SN - 1549-9596

VL - 62

SP - 6788

EP - 6802

JO - Journal of Chemical Information and Modeling

JF - Journal of Chemical Information and Modeling

IS - 24

ER -

Lipid Modulation of a Class B GPCR: Elucidating the Modulatory Role of PI(4,5)P₂ Lipids

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