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. Despite extensive functional and structural studies of alpha-KTx-potassium channel complexes, none have predicted the molecular basis of alpha-KTx specificity. Here we show that by minimizing the differences in binding free energy between selective and nonselective alpha-KTx we are able to identify all of the determinants of alpha-KTx specificity for calcium-activated versus voltage-dependent potassium channels. Because these determinants correspond to unique features of the two types of channels, they provide a way to develop more accurate models of alpha-KTx-potassium channel complexes that can be used to design novel selective alpha-KTx inhibitors.
Giangiacomo
Kathleen M
KM
Biochemistry Department, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, Pennsylvania 19140, USA. giang@ temple.edu
Becker
Jennifer
J
Garsky
Christopher
C
Felix
John P
JP
Priest
Birgit T
BT
Schmalhofer
William
W
Garcia
Maria L
ML
Mullmann
Theodore J
TJ
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D018999:Charybdotoxin / Q000737:chemistry / Q000235:genetics / Q000633:toxicity; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000633:toxicity; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000633:toxicity*; D012604:Scorpion Venoms / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity*
D051664:Kv1.3 Potassium Channel; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D026902:Potassium Channel Blockers; D012604:Scorpion Venoms; C110392:hongotoxin 1; D018999:Charybdotoxin; C064719:iberiotoxin