Can 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. 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.
Department of Physics, Applied Physics and Astronomy, Rensselaer Polytechnic Institute, Troy, New York.
Chris
C
Neale
Department of Physics, Applied Physics and Astronomy, Rensselaer Polytechnic Institute, Troy, New York.
Henry D
HD
Herce
Molecular Structure and Function, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
Régis
R
Pomès
Department of Physics, Applied Physics and Astronomy, Rensselaer Polytechnic Institute, Troy, New York; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York. Electronic address: agarcia@lanl.gov.
Angel E
AE
García
D001665:Binding Sites; D002244:Carbon / Q000737:chemistry; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010100:Oxygen / Q000737:chemistry; D010713:Phosphatidylcholines / Q000737:chemistry; D010715:Phosphatidylglycerols / Q000737:chemistry; D011487:Protein Conformation; D055550:Protein Stability; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*
D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; D018343:Receptors, Adrenergic, beta-2; D002244:Carbon; C060037:1-palmitoyl-2-oleoylglycero-3-phosphoglycerol; D010100:Oxygen; C028694:1-palmitoyl-2-oleoylphosphatidylcholine