CRYSTAL CLEAR Seeing the chemistry within K+ ion channels with great accuracy was made possible by the 2.0-Å resolution achieved with crystals formed by complexing the ion channels (yellow) with fragments of a monoclonal antibody (blue). REPRINTED BY PERMISSION OF NATURE, © 2001

Transport of K⁺ ions through protein channels is fundamental to electrical signaling in biological systems. Three years ago, the structure of a K⁺ ion channel--obtained by a team led by Rockefeller University biophysicist Roderick MacKinnon--yielded clues to the protein's ion selectivity (C&EN, April 6, 1998, page 12). Now, three studies explain how K⁺ ions traverse the channel and the "costume changes" that occur en route.

Two of the studies are based on higher resolution crystal structures of K⁺ ion channels obtained recently by MacKinnon and coworkers Yufeng Zhou, João H. Morais-Cabral, and Amelia Kaufman. The third is based on molecular dynamics simulations by biochemistry professor Benoît Roux and graduate student Simon Bernèche at Weill Medical College of Cornell University [Nature, 414, 37, 43, and 73 (2001)].

The new structures show that a K⁺ ion first enters the channel's cavity covered by an inner hydration shell. This shell, the structures reveal, consists of eight water molecules, four above and four below the cation centered in the cavity.

Next, the ion must traverse a constriction in the channel, called the selectivity filter. It was known that this narrow tunnel cannot accommodate a K⁺ ion dressed up with water molecules; the ion must enter this space "naked." But how the protein extracts a cation from the water and allows it to move through a mostly anhydrous pore while bereft of water was a puzzle that has only now been solved.

	Roux
	MacKinnon PHOTO BY MAIRIN BRENNAN

The selectivity filter is lined with oxygen atoms arranged so that they "mimic the eight water molecules that form the inner hydration shell of a K⁺ ion," explains Christopher Miller, a biochemistry professor at Brandeis University, Waltham, Mass., and author of a Nature commentary on the three papers. "The geometry of the oxygen atoms in the filter is beautifully matched to the geometry of the ion's inner hydration shell," he tells C&EN. So everywhere it turns, a K⁺ ion "sees" the same environment. "That's why it is so willing to shed its water molecules and enter the filter."

The new structures provide snapshots of the K⁺ channel populated with ions. The channel has seven sites for ions: one in the cavity, four in the selectivity filter, and two outside the cell. The last two sites are "the big surprise of the structure," Miller tells C&EN. "It's remarkable that these sites, which are in the solvent, show up in the X-ray structure. They probably are electrostatically suspended there by the influence of the protein. It's as though the protein has a field that concentrates ions right in this area."

Although unexpected, the existence of those sites is predicted by the study of Bernèche and Roux. "Roux had been talking about this more than a year ago, and nobody believed it," Miller recalls. "Now, MacKinnon has seen it."

The simulations of Bernèche and Roux and the structural data agree on how ions move through the four sites in the filter. They go in pairs with a water molecule in between, as had been expected from indirect evidence.

Pairing introduces just enough instability in the filter to keep ions moving. In a space for which it has very high affinity, one ion alone "would be too happy and never get out," Miller explains. Repulsion between the ions reduces that affinity slightly and helps propel the ions out, the simulations show.

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