Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P) 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)P 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)P lipids to GCGR. Specifically, we find the PI(4,5)P 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)P 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)P between class A and class B GPCRs.
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