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Salt Bridge Switching from Arg290/Glu167 to Arg290/ATP Promotes the Closed-to-Open Transition of the P2X2 Receptor
- Source :
- Molecular Pharmacology. 83:73-84
- Publication Year :
- 2012
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2012.
-
Abstract
- P2X receptors are trimeric adenosine-5'-triphosphate (ATP)-gated cation channels involved in fast signal transduction in many cell types. In this study, we used homology modeling of the rat P2X2 receptor with the zebrafish P2X4 X-ray template to determine that the side chains of the Glu167 and Arg290 residues are in close spatial vicinity within the ATP-binding pocket when the rat P2X2 channel is closed. Through charge reversal mutation analysis and mutant cycle analysis, we obtained evidence that Glu167 and Arg290 form an electrostatic interaction. In addition, disulfide trapping indicated the close proximity of Glu167 and Arg290 when the channel is in the closed state, but not in the ATP-bound open state. Consistent with a gating-induced movement that disrupts the Glu167/Arg290 salt bridge, a comparison of the closed and open rat P2X2 receptor models revealed a significant rearrangement of the protein backbone and the side chains of the Glu167 and Arg290 residues during the closed-to-open transition. The associated release of the Glu167/Arg290 salt bridge during channel opening allows a strong ionic interaction between Arg290 and a γ-phosphate oxygen of ATP. We conclude from these results that the state-dependent salt bridge switching from Arg290/Glu167 to Arg290/ATP fulfills a dual role: to destabilize the closed state of the receptor and to promote the ionic coordination of ATP in the ATP-binding pocket.
- Subjects :
- Models, Molecular
Patch-Clamp Techniques
Purinergic P2X Receptor Antagonists
Stereochemistry
Static Electricity
Glutamic Acid
Ionic bonding
Arginine
Purinergic P2X Receptor Agonists
Xenopus laevis
Adenosine Triphosphate
Static electricity
Side chain
Animals
Peptide bond
Homology modeling
Receptor
Pharmacology
Binding Sites
Chemistry
Recombinant Proteins
Rats
Mutation
Mutagenesis, Site-Directed
Oocytes
Molecular Medicine
Female
Salt bridge
Signal transduction
Ion Channel Gating
Receptors, Purinergic P2X4
Receptors, Purinergic P2X2
Subjects
Details
- ISSN :
- 15210111 and 0026895X
- Volume :
- 83
- Database :
- OpenAIRE
- Journal :
- Molecular Pharmacology
- Accession number :
- edsair.doi.dedup.....283f4a405a84e2d8e2dd77e0cf842a46