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Volume 87 Issue 31 | p. 10 | News of The Week
Issue Date: August 3, 2009

Cation Courier

The last family of ligand-gated ion channels reveals its form
Department: Science & Technology
Keywords: ion channel, x-ray crystallography, pain, taste, inflammation
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Two 
transmembrane ion channels 
have different amino acid 
sequences 
but similar topology. One (gold) is switched on by ATP binding, and the other (purple) by 
protons.
Credit: Nature
8731NOTWp10
 
Look-
Alike
Two 
transmembrane ion channels 
have different amino acid 
sequences 
but similar topology. One (gold) is switched on by ATP binding, and the other (purple) by 
protons.
Credit: Nature

An ion channel found in almost every cell of the human body—where it acts as a gatekeeper for positively charged currents that control everything from taste to pain to inflammation—has finally revealed its three-dimensional X-ray structure.

The protein conduit is a member of the P2X family of ion channels, which are inspired to open by the binding of adenosine triphosphate (ATP), a molecule better known for its role as an energy carrier than as an ion-channel-opening switch.

The pharmaceutical industry is trying to develop drugs that interfere with P2X ion channels, and this is the first member of that family to succumb to X-ray crystallography, comments Richard J. Evans, a pharmacologist at the University of Leicester, in England, who studies how P2X channels manipulate blood pressure. Furthermore, P2X channels are the last family of ligand-gated ion channels to yield to structural determination, Evans adds. For years, he says, “people have been hoping the high-resolution structure of a P2X channel would come.”

After seven years of tinkering with the P2X4 channel, a team of researchers, led by crystallographer Eric Gouaux of the Vollum Institute at Oregon Health & Science University, finally solved the structure of the membrane protein in the closed conformation (Nature 2009, 460, 599). The Gouaux group also reports the 3-D structure of an acid-sensing, proton-gated ion channel and shows that the ATP- and proton-gated ion channels have similar overall architectures, despite the fact that the amino acid sequences of both proteins share almost no similarity (Nature 2009, 460, 592).

Both ion channels have an hourglass structure. The two proteins also contain similar “vestibules,” which are interior compartments lined with negatively charged amino acids that likely entice positively charged cations into the pore, Gouaux says.

Gouaux hopes the structures will aid the development of new compounds to modulate, inhibit, or activate the channels. Such compounds, he adds, “might prove useful as therapeutic agents.”

 
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