“This is an important work demonstrating for the first time the architecture of the nicotinic acetylcholine receptor membrane pore.”

This paper represents only one part of a 4Ĺ resolution electron microscopy structure, namely the transmembrane region of the acetylcholine receptor. However, even this partial structure is of great interest. It is one of the most studied synaptic receptors, and the family of proteins—the ligand-gated ion channels family—is the second most important drug target, after G-protein coupled receptors. This is the first structural paper that actually claims the resolution to make conclusions about the placement and role of specific residues of the acetylcholine receptor. Thus, this paper presents a large number of chances for immediately testing the conclusions. This is a strong and intensely exciting feature. The correct atomic structure can greatly aid many of the researchers in the field.

This work convincingly describes the overall structure of the receptor, in particular:

1. Each transmembrane segment folds entirely into an α-helix, a feature that was a matter of controversy in the literature.
2. The helices protrude 10Ĺ above the 30Ĺ thick membrane, in such a way that the domain shaping the lumen is longer than commonly assumed.
3. The outer helices tilt around the central axis, giving rise to a left-handed coil.
4. Helices are splayed apart on the extracellular side of the membrane, putatively creating alternative routes for the ions toward the channel.
5. A gating mechanism between the extracellular and transmembrane domains is proposed.

This is an important work which demonstrates for the first time the architecture of the nicotinic acetylcholine receptor membrane pore and its gating mechanism. This is the continuation of a very long-term project of over 20 years duration which uses electron microscopy to analyze the helical tubular crystal of the receptor. The use of the electron microscope with a liquid helium cooling stage, the computational correction of the image distortion, and real-space averaging of data from different helical families has provided a complete picture of the receptor. The structure now proposed makes sense when compared with biochemical and functional data.

Professor Yoshinori Fujiyoshi at Kyoto University, my supervisor, had been in close contact with Dr. Nigel Unwin at MRC-LMB in Cambridge. Because of this association, I was able to join Dr. Unwin’s laboratory as a postdoc for three years (1995-1998) to work in the long-term project of structure analysis of the acetylcholine receptor by cryo-electron microscopy. After I came back to Japan, Dr. Unwin kindly allowed me to maintain a close collaboration between his lab and ours. Prof. Fujiyoshi has been strongly supportive of this work from the very beginning. During our long-distance collaboration, he has greatly helped us to gather the best possible images by the utilization of the best cryo-electron microscope in the world, which he developed himself. Dr. Unwin has been inching toward the accomplishment of getting the complete atomic model of the receptor for more than 20 years and he is to be congratulated for his efforts.