Novel treatments for high blood pressure and other disorders could emerge from high-resolution solid-state NMR studies that reveal how toxins affect the structure of potasssium channels in the cell.

Marc Baldus of the Max Planck Institute for Biophysical Chemistry in Göttingen and colleagues in France and Germany have exploited a special protein synthesis procedure to follow how potassium channels and toxins combine to change the structure of the channel.

Crystallography has taken great strides in our understanding of cellular membrane "ion channels". However, the dynamic structural details of interactions with other compounds have remained elusive. Different channels are open to specific ions. For instance, potassium channels only transport potassium ions. One clue to understanding ion channels lies in the fact that certain toxins produced by venomous animals, such as the kaliotoxin produced by the African scorpion (Androctonus mauretanicus mauretanicus) can also target these channels so blocking the flow of normal ions, and often killing the cell.

The MPI team working with colleagues at the Institute for Neural Signal Processing in Hamburg and the University of Marseille have looked at how bacterial potassium channels interact with the scorpion toxin at the atomic level. First, the team examined the electrophysiological characteristics of the "poisoned" channel protein. The researchers then spin-marked some of them and used solid-state NMR to observe the changes.

The spectroscopic data before and after cellular intoxication revealed how the poison attaches to the pore region and distorts the pore's structure. The implication is that the toxin is effective only when it recognises and attaches to a particular amino acid sequence in the ion channel. The study also reveals that the toxin itself has to be flexible in order for the interaction to take place. It's almost as if a flexible key were being inserted into a flexible lock. The researchers propose that the structural flexibility of both the potassium channel and the toxin "represent an important determinant for the high specificity of toxin-K⁺ channel interactions."

Baldus and colleagues add that their finding could be used in drug discovery. "The application of ssNMR spectroscopy presented here can be exploited to advance current structure-based design studies, leading to novel therapeutic agents in potassium ion pharmacology," they say.

Related links:

• Nature, 2006, 440, 959-962
• Baldus Page 

Article by David Bradley