Garcia Research Group

Specific Protein-Lipid Interactions Stabilize an Active State of the Beta 2 Adrenergic Receptor

G protein-coupled receptors are eukaryotic membrane proteins with broad biological and pharmacological relevance. Like all membrane-embedded proteins, their location and orientation are influenced by lipids, which can also impact protein function via specific interactions. Our extensive (0.25 millisecond) simulations reveal a mechanism in which phospholipids from the membrane's cytosolic leaflet invade the empty G protein binding site of an activated beta 2 adrenergic receptor and form salt-bridge interactions that inhibit ionic lock formation and prolong active-state residency. Simulations of the receptor embedded in an anionic membrane show increased lipid binding, providing a molecular mechanism for the experimental observation that anionic lipids can enhance receptor activity. Conservation of the arginine component of the ionic lock among Rhodopsin-like G protein-coupled receptors suggests that intracellular lipid ingression between receptor helices H6 and H7 may be a general mechanism for active-state stabilization.

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