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

• Published in: Biophysical journal Vol. 109; no. 8; pp. 1652 - 1662
• Main Authors: Neale, Chris, Herce, Henry D., Pomès, Régis, García, Angel E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.10.2015; Biophysical Society; The Biophysical Society
• Subjects: Binding Sites; Carbon - chemistry; Eukaryotes; Humans; Lipid Bilayers - chemistry; Lipids; Membranes; Molecular Dynamics Simulation; Mutation; Oxygen - chemistry; Phosphatidylcholines - chemistry; Phosphatidylglycerols - chemistry; Protein Conformation; Protein Stability; Proteins; Receptors, Adrenergic, beta-2 - genetics; Receptors, Adrenergic, beta-2 - metabolism; Simulation
• ISSN: 0006-3495; 1542-0086; 1542-0086
• DOI: 10.1016/j.bpj.2015.08.028

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. Extensive simulations totaling 0.25 ms reveal a process in which phospholipids from the membrane’s cytosolic leaflet enter the empty G-protein binding site of an activated β2 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.