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 af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

12 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Journal of Chemical Information and Modeling
Vol/bind	62
Nummer	24
Sider (fra-til)	6788-6802
Antal sider	15
ISSN	1549-9596
DOI	https://doi.org/10.1021/acs.jcim.2c00635
Status	Udgivet - dec. 2022

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10.1021/acs.jcim.2c00635

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Citationsformater

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

language = "English",

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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

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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.

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KW - Lipids/chemistry

KW - Molecular Conformation

KW - Molecular Dynamics Simulation

KW - Receptors, G-Protein-Coupled/chemistry

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