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An essential binding surface for ShK toxin interaction with rat brain potassium channels
M W Pennington1, V M Mahnir, I Khaytin
1Bachem Bioscience Inc., King of Prussia, Pennsylvania 19406, USA. mpennipep@aol.com
Biochemistry
|December 24, 1996
Summary
ShK toxin binding to brain potassium channels depends on specific residues. Tyr23 is crucial for affinity, while Lys22 and Tyr23 form key interactions on the binding surface.
Area of Science:
- Biochemistry
- Molecular Biology
- Neuroscience
Background:
- ShK toxin is a peptide that interacts with brain delayed rectifier potassium channels.
- Understanding these interactions is key to deciphering potassium channel function and pharmacology.
Purpose of the Study:
- To identify critical residues in ShK toxin responsible for binding to delayed rectifier potassium channels.
- To elucidate the specific roles of residues, particularly Tyr23, in toxin-channel interactions.
Main Methods:
- "Ala scan" analysis of ShK toxin analogs.
- Synthesis and testing of additional ShK toxin analogs.
- Measurement of inhibitory effects on 125I-labeled dendrotoxin binding to rat brain membranes.
Main Results:
- Seven side chains influence ShK toxin binding to potassium channels.
- Replacement of Tyr23 with Ala drastically reduced toxin affinity for Kv1.2 channels.
- Aromaticity at Tyr23 is vital for binding; aromaticity at Phe27 is less critical.
Conclusions:
- The binding surface of ShK toxin involves residues Ile7, Arg11, Ser20, Lys22, Tyr23, and Phe27.
- Lys22 and Tyr23 are major contributors to binding through ionic and aromatic interactions.
- Aromaticity at position 23 is essential for effective binding to delayed rectifier brain K channels.