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Sodium Ion Binding Pocket Mutations and Adenosine A~2A~Receptor Function by Arnault Massink; Hugo Gutiérrez-de-Terán; Eelke B. Lenselink; Natalia V. Ortiz Zacarías; Lizi Xia; Laura H. Heitman; Vsevolod Katritch; Raymond C. Stevens; Adriaan P. IJzerman is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

What is Sodium Ion Binding Pocket Mutations and Adenosine A~2A~Receptor Function about?

Recently we identified a sodium ion binding pocket in a high-resolution structure of the human adenosine A2A receptor. In the present study we explored this binding site through site-directed mutagenesis and molecular dynamics simulations. Amino acids in the pocket were mutated to alanine, and their influence on agonist and antagonist affinity, allosterism by sodium ions and amilorides, and receptor functionality was explored. Mutation of the polar residues in the Na(+) pocket were shown to either abrogate (D52A(2.50) and N284A(7.49)) or reduce (S91A(3.39), W246A(6.48), and N280A(7.45)) the negative allosteric effect of sodium ions on agonist binding. Mutations D52A(2.50) and N284A(7.49) completely abolished receptor signaling, whereas mutations S91A(3.39) and N280A(7.45) elevated basal activity and mutations S91A(3.39), W246A(6.48), and N280A(7.45) decreased agonist-stimulated receptor signaling. In molecular dynamics simulations D52A(2.50) directly affected the mobility of sodium ions, which readily migrated to another pocket formed by Glu13(1.39) and His278(7.43). The D52A(2.50) mutation also decreased the potency of amiloride with respect to ligand displacement but did not chan

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Author

Arnault Massink; Hugo Gutiérrez-de-Terán; Eelke B. Lenselink; Natalia V. Ortiz Zacarías; Lizi Xia; Laura H. Heitman; Vsevolod Katritch; Raymond C. Stevens; Adriaan P. IJzerman

Publisher

American Society for Pharmacology & Experimental Therapeutics (ASPET)

Published

2014

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)