Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
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Influence of Lipid Composition on the Structural Stability of G-Protein Coupled Receptor
Md. Iqbal MahmoodXinli LiuSaburo NeyaTyuji Hoshino
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2013 Volume 61 Issue 4 Pages 426-437


β2 Adrenergic receptor (β2AR) is a kind of G-protein coupled receptors (GPCRs) which transduce a wide range of extracellular signals into intracellular messages responsible for the regulation of diverse cell functions. Because of their functional ubiquity, GPCR is one of the most important drug targets in pharmaceutical industry. Although recent crystallographic studies provided both the active and the inactive states of some families of GPCRs, the influence of lipid composition of bilayer membrane on their activation is still poorly understood. In this work, we address the influence of lipid composition on the structural stability of GPCR, performing molecular dynamics simulations of three kinds of states: apo-, and agonist epinephrine-, or antagonist alprenolol-bound β2AR. These three kinds of β2ARs were embedded in four types of lipid membranes: (i) pure palmitoyl-oleoyl-phosphatidyl-choline (POPC), (ii) POPC/cholesterol (CHL), (iii) POPC/CHL/GM1 (GM1 ganglioside), (iv) POPC/palmitoyl-oleoyl-phosphatidyl-ethanolamine (POPE)/CHL/sphingomyeline (SM). The side chains of Lys2676.29 and Asp3317.58 showed different conformations among the three states in all types of lipid membranes. The distances between Lys2676.29 and Asp3317.58 of apo- and alprenolol-bound β2ARs are smaller than that of the epinephrine-bound β2AR. In contrast, β2ARs in POPC/CHL bilayer were unstable in which the salt bridge; i.e., ionic lock, was not formed between Arg1313.50 and Glu2686.30. We have also examined the distribution of lipid molecules. A stable hydrophobic interaction between CHL and β2AR was observed at transmembrane helix5 in POPC/CHL/GM1 and POPC/POPE/CHL/SM membranes. These results suggest that the lipid composition strongly affects the conformation of GPCR and essentially concerns the GPCR activation.

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© 2013 The Pharmaceutical Society of Japan
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