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. The alpha-KTx subfamilies 1-3, display gross differences in specificity for maxi-K vs. KV channels. However, many potassium channels are largely untouched by alpha-KTx's. Differences in toxin binding free energy provide a quantitative framework for defining specificity. As a practical criterion for specificity a minimum binding free energy difference of 2.72 kcal/mol is proposed. Binding free energy differences for wild-type and mutant toxins and channels can point to amino acids underlying specificity and to unique features of potassium channel outer pores. Known 3D structures of potassium channels in combination with CLUSTALW sequence alignment of over 60 potassium channels reveal significant variation in alpha-KTx binding domains. Structure-based homology models of potassium channels complexed with alpha-KTxs, in combination with measurements of toxin binding free energy, will further our understanding of the molecular basis of alpha-KTx specificity.
Giangiacomo
Kathleen M
KM
Department of Biochemistry, Temple University School of Medicine, 3420 N. Broad Street, Philadelphia, PA 19140, USA. glang@temple.edu
Ceralde
Yamille
Y
Mullmann
Theodore J
TJ
D000595:Amino Acid Sequence; D000818:Animals; D008969:Molecular Sequence Data; D026902:Potassium Channel Blockers / Q000378:metabolism*; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D012604:Scorpion Venoms / Q000378:metabolism*; D012605:Scorpions / Q000737:chemistry*; D016415:Sequence Alignment; D013379:Substrate Specificity / Q000502:physiology
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D012604:Scorpion Venoms