STRUCTURE-ACTIVITY RELATIONSHIP STUDY OF A SCORPION TOXIN WITH HIGH-AFFINITY FOR APAMIN-SENSITIVE POTASSIUM CHANNELS BY MEANS OF THE SOLUTION STRUCTURE OF ANALOGS

Scorpion venoms contain numerous toxic polypeptides displaying various pharmacological activities. These toxins interact with ion channels o f excitable membranes. Long toxins (60-70 amino acids) are known to in teract with sodium channels, whereas most of the short toxins (31-37 a mino acids) found their toxicity in modifying the potassium channel fu nctions. A family of short scorpion toxins are known to interact speci fically with apamin-sensitive calcium-activated potassium channels. St ructure-activity relationship studies of these toxins have demonstrate d that a short region located on the solvent-exposed side of an alpha- helix is involved in the interaction with their receptor. Two position s, i.e. residues 6 and 7 in the sequence, are essential for the full a ctivity of these molecules. We have synthesized analogues of these tox ins and demonstrated that the three-dimensional structure is not affec ted by these mutations, and thus that the observed variations of activ ity are only due to the chemical function carried by the side chain. T his interaction between the toxins and their receptor is thus purely e lectrostatic. (C) Munksgaard 1995.