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  • Review Article
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Ion channel structure

Potassium channel structures

Key Points

  • Our understanding of the workings of K+ channels has been furthered by the determination of the crystal structure of the bacterial channel KcsA. In particular, the structure of KcsA has provided us with new insights into the atomic basis of ion selectivity and permeation.

  • Ion selectivity takes place at the narrowest part of the ion permeation pathway — the selectivity filter. The crystal structure of KcsA has shown that the filter is about 12-Å long and 2.5 Å in diameter. The principal constituents of the filter are main-chain carbonyl oxygens from amino-acid residues of the P loop.

  • There are six K+-binding sites along the filter — four internal (P1–P4) and two external (P0 and P5). Each of these binding sites consists of eight oxygen atoms that coordinate a K+ ion. The fact that this coordination geometry is conserved in and out of the pore provides strong support for the idea that the hydration shell of the cation is replaced with pore oxygens as it permeates through the channel.

  • The filter can harbour two K+ ions simultaneously, either at P1 and P3, or at P2 and P4. A transition between these two configurations can be initiated by a third ion entering the pore. As comparable levels of occupancy are observed at all four sites, it has been suggested that the energetic barrier between the two configurations is very low. A dynamic model of permeation has confirmed this suggestion.

  • Channel gating has been studied in most detail in voltage-gated channels. In the case of this subfamily, channel opening is intimately coupled to the S4 transmembrane helix, which undergoes conformational changes in response to membrane voltage.

  • How are changes in S4 translated at the permeation pathway such that ion flow can proceed? When the 2TM/P core of a voltage-gated K+ channel is replaced by the equivalent part of KcsA, the chimeric channel is sensitive to voltage. But to accomplish this coupling, the chimera must include cytoplasmic segments of the transmembrane helices S5 and S6. So, conformational changes at the junction between the transmembrane and cytoplasmic domains of the channel are crucial for coupling between voltage sensing and gating.

  • The tetramerization domain, T1, is at the amino-terminal domain of the channel. Structural analyses of T1 domains from different K+ channels have provided insights into the structural basis of channel assembly. In particular, a water-filled cavity exists at the centre of a T1 tetramer, but this cavity is not part of the ion-permeation pathway. Instead, the cytoplasmic vestibule of the channel seems to lie between the membrane-facing side of T1 and the inner leaflet of the membrane.

  • Inactivation takes place when the ball peptide, a 30-amino-acid stretch that is present at the amino-terminal end of the channel protein, effectively plugs the channel mouth. To plug the permeation pathway, the inactivation ball might reach the pore through one of the lateral openings of the vestibule as an unfolded polypeptide chain. Alternatively, the inactivation peptide might be bound elsewhere in the channel before it disengages to reach its binding site.

  • Channel function can be regulated through protein–protein interactions. There are many examples of channel regulation by signalling pathways, such as the regulation of Kir3 by G-protein-coupled receptors, and the regulation of Kv1.5 by Src and tyrosine kinase receptors. Similarly, Kv4 is phosphorylated by mitogen-activated protein kinase, and is regulated by a versatile protein known as KchIP, which enhances its inactivation and recovery rates.


The molecular basis of K+ channel function is universally conserved. K+ channels allow K+ flux and are essential for the generation of electric current across excitable membranes. K+ channels are also the targets of various intracellular control mechanisms, such that the suboptimal regulation of channel function might be related to pathological conditions. Because of the fundamental role of K+ channels in controlling membrane excitability, a structural understanding of their function and regulation will provide a useful framework for understanding neuronal physiology. Many recent physiological and crystallographic studies have led to new insights into the workings of K+ channels.

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Figure 1: The four main classes of potassium channel.
Figure 2: Composite structure of voltage-gated K+ channels.
Figure 3: Model for the molecular motion associated with voltage-mediated gating.

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The work in the author's laboratory has been supported by the National Institutes of Health, the American Heart Association and the Klingenstein Foundation. The work on T1 has been a long-term collaboration with Paul Pfaffinger's laboratory at the Baylor College of Medicine.

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Protein Families Database

PF02254: KTN NAD-binding domain 

Protein Data Bank

1BL8: potassium channel (KcsA)


ion channels

sodium, calcium and potassium channels

voltage-gated potassium channels 

Families of Transport Proteins

The Ion Channel Web Page



In an ion channel, the P loop is a short amino-acid segment between two transmembrane helices that dips into the membrane without fully crossing it. The primary sequence of the P loop of K+ channels has the signature sequence Thr–Val–Gly–Tyr–Gly.


Potassium channels that allow long depolarizing responses, as they close during depolarizing pulses and open with steep voltage dependence on hyperpolarization. They are called inward rectifiers because current flows through them more easily into than out of the cell.


Potassium channels that are regulated by calcium. As their unitary conductance is big, they are called BK to distinguish them from SK channels, a different population of calcium-regulated channels with smaller conductance. In neurons, BK channels colocalize with calcium channels, shape action potential waveforms and regulate transmitter release.


The part of an amino acid (NH3+ and COO) that forms a covalent link with the next amino acid on a polypeptide chain.


The part of an amino acid that extends from the α-carbon atom that is unique for that amino acid.


Nuclear magnetic resonance. A technique used to determine the content, purity and molecular structure of a sample. This method is based on the fact that some atomic nuclei have a magnetic moment. When these nuclei are placed in a magnetic field and are simultaneously exposed to electromagnetic radiation, they change their energy state and absorb energy.


The generation of a mutation at a predetermined position in a DNA sequence. The most common method involves the use of a chemically synthesized mutant DNA strand that can hybridize with the target molecule.


A term originally used to describe enzymes that have two or more receptor sites, one of which (the active site) binds the principal substrate, whereas the other(s) bind(s) effector molecules that can influence its biological activity. More generally, it is used to describe the indirect coupling of distinct sites within a protein, mediated by conformational changes.


The first proto-oncogene to be identified. It codes for a non-receptor protein tyrosine kinase.


Any of a family of protein kinases that are important for relaying signals from the cell membrane to the nucleus.

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Choe, S. Potassium channel structures. Nat Rev Neurosci 3, 115–121 (2002).

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