The recent publication of the crystal structure of a voltage-gated K+ channel is an important milestone in the study of ion channel function on at least two counts. First, it brings years of discussion on the actual structure of K+ channels to an end. Second, it shows that our previous structural conception of the gating process, which was developed largely on the basis of structure–function studies, is fundamentally wrong.

K+-channel gating. a | Corkscrew model. b | Paddle model. c | Ribbon diagram of the KvAP structure in the closed state. The voltage-sensor paddle is shown in red. d | KvAP in the open state, showing the large displacement of the paddle. Reproduced, with permission, from Jiang et al. Nature © (2003) Macmillan Magazines Ltd.

Jiang et al. solved the crystal structure of KvAP, an archaebacterial channel that is closely related to eukaryotic K+ channels. Not unexpectedly, they found that the pore region (the P loop and the S5 and S6 transmembrane domains) of KvAP was quite similar to that of KcsA, another bacterial channel for which we have structural information. The unexpected finding came from the analysis of the rest of the protein.

Until now, the accepted structural model of voltage-gated K+ channels stated that S1–S4 were transmembrane helices and, owing to the presence of a series of charged residues, S4 was identified as the voltage sensor. In response to voltage changes, S4 was thought to rotate like a corkscrew inside the membrane, protected from the hydrophobic lipid environment by S1–S3, and this rotation was thought to be linked somehow to channel opening. As it turns out, the X-ray data showed that S4 is perpendicular to the ion-conduction pathway, close to the intracellular face of the channel, and tightly packed against the carboxy-terminal part of S3, forming what the authors refer to as the voltage-sensor paddle. This paddle is linked to the rest of the channel through flexible loops, indicating that it might move through the membrane. This observation raises the possibility that this motion is coupled to the movements of S5 and the rest of the ion-conduction pathway, leading to channel opening.

In a companion article, Jiang et al. explored the validity of this radically different gating model by replacing different residues of the paddle with cysteine, biotinylating this amino acid, and testing whether avidin, a molecule with high affinity for biotin, would bind the paddle extra- or intracellularly during channel opening. They found that avidin could bind to the S3 residues only from the outside of the cell and only if the channel was open. In the case of S4, avidin had access to some residues only from the outside (upon channel opening), to others only from the inside (when the channel was closed) and to a third class from both sides. These data imply that the paddle indeed experiences a large displacement across the lipid bilayer following voltage changes. This movement might simply pull the S5 domain to open the channel.

So, K+-channel gating involves a fundamentally different operational principle that could not have emerged from mutational analysis alone. The publication of these two papers constitutes an important landmark for the field and will undoubtedly be hailed as one of the breakthroughs of the year.