Abstract
Several aminergic GPCRs, e.g., the human histamine H-3-receptor (hH(3)R) are sensitive to sodium ions. Based on these experimental results, including site directed mutagenesis studies, a sodium binding pocket near to the highly conserved Asp(2.50) was suggested. Recently, in the crystallized adenosine A(2A) receptor (4EIY), a sodium ion was found in a pocket, coordinated by Asp(52), Ser(91), and ...
Abstract
Several aminergic GPCRs, e.g., the human histamine H-3-receptor (hH(3)R) are sensitive to sodium ions. Based on these experimental results, including site directed mutagenesis studies, a sodium binding pocket near to the highly conserved Asp(2.50) was suggested. Recently, in the crystallized adenosine A(2A) receptor (4EIY), a sodium ion was found in a pocket, coordinated by Asp(52), Ser(91), and three water molecules. Despite high homology in amino acid sequence between hH(3)R and hH(4)R, pharmacological studies revealed that the hH(4)R is-in contrast to hH(3)R - not sensitive to sodium ions. In order to obtain a deeper insight onto the differences in sodium sensitivity between hH(3)R and hH(4)R, we performed molecular modelling studies, including molecular dynamic simulations and calculation of Gibbs energy of solvation. The results of the modeling studies suggested that the amino acid at position 7.42 influences sodium binding to aminergic GPCRs in different ways. A comparison of the amino acids forming the sodium binding channel between the ligand binding pocket and the sodium binding pocket of all human aminergic GPCRs showed an 80 % occurrence of glycine - in contrast to hH(3)R and hH(4)R. The Gln(7.42) at hH(4)R disrupts a water chain, connecting the Asp(3.32) of the orthosteric binding site and the Asp(2.50) of the allosteric binding site. Besides, the oxygen of the glutamine side chain stabilizes the interaction of the sodium ion with the Asp(3.32). Thus, the binding of the sodium into the allosteric binding site might be hindered kinetically.
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