C-Terminal residues in small potassium channel blockers OdK1 and OSK3 from scorpion venom fine-tune the selectivity.
We report isolation, sequencing, and electrophysiological characterization of OSK3 (α-KTx 8.8 in Kalium and Uniprot databases), a potassium channel blocker from the scorpion Orthochirus scrobiculosus venom. Using the voltage clamp technique, OSK3 was tested on a wide panel of 11 voltage-gated potassium channels expressed in Xenopus oocytes, and was found to potently inhibit Kv1.2 and Kv1.3 with IC50values of ~331nM and ~503nM, respectively. OdK1 produced by the scorpion Odontobuthus doriae differs by just two C-terminal residues from OSK3, but shows marked preference to Kv1.2. Based on the charybdotoxin-potassium channel complex crystal structure, a model was built to explain the role of the variable residues in OdK1 and OSK3 selectivity.
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia; Biological Faculty, Lomonosov Moscow State University, Moscow 119992, Russia. Electronic address: aleksey.kuzmenkov@gmail.com.
Alexey I
AI
Kuzmenkov
Toxicology and Pharmacology, University of Leuven, Leuven 3000, Belgium.
Steve
S
Peigneur
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia; National Research University Higher School of Economics, Moscow, 101000, Russia.
Anton O
AO
Chugunov
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia.
Valentin M
VM
Tabakmakher
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia; National Research University Higher School of Economics, Moscow, 101000, Russia.
Roman G
RG
Efremov
Toxicology and Pharmacology, University of Leuven, Leuven 3000, Belgium.
Jan
J
Tytgat
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia.
Eugene V
EV
Grishin
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia; Biological Faculty, Lomonosov Moscow State University, Moscow 119992, Russia. Electronic address: avas@ibch.ru.
Alexander A
AA
Vassilevski
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D018360:Crystallography, X-Ray; D004594:Electrophysiology; D051663:Kv1.2 Potassium Channel / Q000037:antagonists & inhibitors / Q000737:chemistry; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000737:chemistry; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000737:chemistry / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism; D011487:Protein Conformation; D012604:Scorpion Venoms / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D012605:Scorpions / Q000737:chemistry / Q000378:metabolism; D014981:Xenopus / Q000235:genetics
C515957:K1 toxin, Odonthobuthus doriae; D051663:Kv1.2 Potassium Channel; D051664:Kv1.3 Potassium Channel; C000621254:OdK3 protein, Odonthobuthus doriae; D026902:Potassium Channel Blockers; D012604:Scorpion Venoms; D011188:Potassium
Cysteine-stabilized α/β fold (CSα/β); KTx; Pore blockers; Scorpion toxins; Voltage-gated potassium channels