The Three Dimensional Structure of Ion Channels

The final frontier is to be able to visualize the three-dimensional structure of ion channels. In 1998, Rod MacKinnon and colleagues reported the three-dimensional structure of a potassium channel and Doug Rees and colleagues reported the structure of a mechan-osensitive channel using X-ray crystallography. Highresolution structural studies of ion channels are difficult to perform because it is difficult to obtain sufficient quantities of ion channel protein for crystallization experiments and it is harder to coax membrane proteins into forming crystals than it is to coax soluble proteins. Both MacKinnon and Rees used bacterial ion channels that are easier to produce recombinantly.

Rod MacKinnon and colleagues determined the structure of the KcsA potassium channel from the bacteria Streptomyces lividans (Fig. 9a). KcsA has two transmembrane segments, which might place it in the same category as inward rectifier potassium channels. However, sequence analysis ofKcsA suggests that it is more closely related to voltage-gated potassium channels than inward rectifiers. In support of this view, KcsA interacts with a peptide toxin, agitoxin2, that blocks Shaker but not inward rectifiers. One of the most satisfying aspects of the channel structure has been how well it agrees with predictions from functional studies of potassium channels. The structure is 45 A long and the pore is narrow at the top, where the selectivity filter is predicted to be located. The helical structure resembles an ''inverted teepee,'' and in the center of the ion channel there is a wide cavity that MacKinnon refers to as the ''lake.'' As predicted by earlier experiments, the ion selectivity filter is formed from residues in the P region, and the carbonyl oxygens of GYG are held at a diameter that is optimal for allowing K+ to pass. Previously we stated that ion channels catalyze the transfer of ions across an electrostatic barrier, the plasma membrane. The KcsA structure depicts two elegant mechanisms by which an ion channel overcomes the barrier. First, a water-filled lake reduces the electrostatic barrier by simply surrounding the ion in an aqueous environment. Second, the negative ends of the dipoles formed by four pore helices point toward the center of the lake, forming a point of negative electrostatic potential in the center of the membrane that is favorable for a cation.

Doug Rees and colleagues determined the structure of a mechanosensitive ion channel, MscL, from Mycobacterium tuberculosis (Fig. 9b). MscL is activated when lateral tension is applied to the lipid bilayer and is used by bacteria to rapidly release intracellular solutes when they are placed in a hypoosmotic environment. One motivation for studying MscL was to understand how mechanical stress could gate this ion channel. Since the open MscL channel has been shown to be able to pass a whole protein, thioredoxin, it is likely that the structure in Fig. 9b represents the closed channel. It is possible that normally lateral pressure in the membrane clamps the ion channel shut. When this pressure is released, MscL may expand into the open state.

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