Activation Mechanisms of the First Sphingosine-1-Phosphate Receptor

作者：Caliman Alisha D^*; Miao Yinglong; McCammon J Andrew

来源：Protein Science, 2017, 26(6): 1150-1160.

DOI：10.1002/pro.3165

• GPCR
• S1PR(1)
• molecular dynamics
• activation

Activation of the first sphingosine-1-phosphate receptor (S1PR(1)) promotes permeability of the blood brain barrier, astrocyte and neuronal protection, and lymphocyte egress from secondary lymphoid tissues. Although an agonist often activates the S1PR(1), the receptor exhibits high levels of basal activity. In this study, we performed long-timescale molecular dynamics and accelerated molecular dynamics (aMD) simulations to investigate activation mechanisms of the ligand-free (apo) S1PR(1). In the aMD enhanced sampling simulations, we observed four independent events of activation, which is characterized by close interaction between Y311(7.53) and Y221(5.58) and increased distance between the intracellular ends of transmembrane (TM) helices 3 and 6. Although TM helices TM3, TM6, TM5 and, TM7 are associated with GPCR activation, we discovered that their movements are not necessarily correlated during activation. Instead, TM5 showed a decreased correlation with each of these regions during activation. During activation of the apo receptor, Y221(5.58) and Y311(7.53) became more solvated, because a water channel formed in the intracellular pocket. Additionally, a lipid molecule repeatedly entered the receptor between the extracellular ends of TM1 and TM7, providing important insights into the pathway of ligand entry into the S1PR(1).

• 出版日期2017-6