Phosphatidylinositol 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 existing in class B GPCRs. For class B GPCRs, previous molecular dynamics (MD) studies have shown PI(4,5)P2 interacting with the Glucagon receptor (GCGR), an important target for diabetes and obesity therapeutics. In this work, we combine native mass spectrometry (nMS) with MD simulations to study lipids interactions with GCGR. We demonstrate a preferential binding of the stearic and arachidonic tails (18:0/20:4) of PI(4,5)P2 over other lipid tails, and show how different tail compositions modulate the dynamics of GCGR. Interestingly, we show find that in contrast to class A GPCRs, (16:0/18:1) PI(4,5)P2 stabilizes an inactive conformation of GCGR through a binding site conserved across class B GPCRs but absent in class A GPCRs. This suggests different regulatory functions of PI(4,5)P2 on with class A and class B GPCRs

Lipid modulation of a class B GPCR: Integrating native mass spectrometry with molecular dynamics simulations

ACS Fall 2021

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