Novel alpha-KTx sites in the BK channel and comparative sequence analysis reveal distinguishing features of the BK and KV channel outer pore.

The alpha-KTx peptide toxins inhibit different types of potassium channels by occluding the outer channel pore composed of four identical alpha subunits. The large-conductance, calcium-activated (BK or Slo1) and voltage-dependent (KV) potassium channels differ in their specificity for the different alpha-KTx subfamilies. While many different alpha-KTx subfamilies of different sizes inhibit KV1 channels with high affinity, only one subfamily, alpha-KTx 1.

Revealing the molecular determinants of neurotoxin specificity for calcium-activated versus voltage-dependent potassium channels.

Potassium channel dysfunction underlies diseases such as epilepsy, hypertension, cardiac arrhythmias, and multiple sclerosis. Neurotoxins that selectively inhibit potassium channels, alpha-KTx, have provided invaluable information for dissecting the contribution of different potassium channels to neurotransmission, vasoconstriction, and lymphocyte proliferation. Thus, alpha-KTx specificity comprises an important first step in potassium channel-directed drug discovery for these diseases.

Molecular basis of alpha-KTx specificity.

Potassium channel inhibitor peptides from scorpion venom, alpha-KTx, have greatly advanced our understanding of potassium channel structure and function, Because of their high affinity interaction with the outer pore, alpha-KTx's have aided, in identification of amino acids lining the pore and of proteins constituting functional channels. The alpha-KTx's display a large range of affinities for different potassium channels with differences in binding free energy exceeding approximately 8 kcal/mol. These differences in affinities are the foundation of alpha-KTx specificity and have aided in revealing the physiological and patho-physiological roles of potassium channels.

Glycine 30 in iberiotoxin is a critical determinant of its specificity for maxi-K versus K(V) channels.

Iberiotoxin (IbTX) is a remarkably selective alpha-K toxin peptide (alpha-KTx) inhibitor of the maxi-K channel. In contrast, the highly homologous charybdotoxin inhibits both the maxi-K and K(V)1.3 channels with similar high affinity.

Structural basis for alpha-K toxin specificity for K+ channels revealed through the solution 1H NMR structures of two noxiustoxin-iberiotoxin chimeras.

Noxiustoxin (NxTX) and iberiotoxin (IbTX) exhibit extraordinary differences in their ability to inhibit current through the large-conductance calcium-activated potassium (maxi-K) and voltage-gated potassium (Kv1.3) channels. The three-dimensional structures of NxTX and IbTX display differences in their alpha/beta turn and in the length of the alpha-carbon backbone.