کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
11025772 | 1666518 | 2018 | 44 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
KV1.2 channel-specific blocker from Mesobuthus eupeus scorpion venom: Structural basis of selectivity
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کلمات کلیدی
CAVMBPICKChTxKTxTFATrifluoroacetic acid - اسید TrifluoroaceticScorpion toxin - توکسین عقربMolecular dynamics - دینامیک ملکولی یا پویایی مولکولیReverse-phase - فاز معکوسNav - نهNeurotoxin - نوروتوکسینmaltose binding protein - پروتئین متصل به مالتوزPeptides - پپتیدهاcharybdotoxin - چاریبدوتوکسینvoltage-gated sodium channel - کانال سدیم ولتاژPotassium channel - کانال پتاسیمVoltage-gated potassium channel - کانال پتاسیم با ولتاژvoltage-gated calcium channel - کانال کلسیم با ولتاژIon channel - کانال یونیInhibitor cystine knot - گره سیستین بازدارنده
موضوعات مرتبط
علوم زیستی و بیوفناوری
علم عصب شناسی
علوم اعصاب رفتاری
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Scorpion venom is an unmatched source of selective high-affinity ligands of potassium channels. There is a high demand for such compounds to identify and manipulate the activity of particular channel isoforms. The objective of this study was to obtain and characterize a specific ligand of voltage-gated potassium channel KV1.2. As a result, we report the remarkable selectivity of the peptide MeKTx11-1 (α-KTx 1.16) from Mesobuthus eupeus scorpion venom to this channel isoform. MeKTx11-1 is a high-affinity blocker of KV1.2 (IC50 â¼0.2â¯nM), while its activity against KV1.1, KV1.3, and KV1.6 is 10â¯000, 330 and 45â¯000 fold lower, respectively, as measured using the voltage-clamp technique on mammalian channels expressed in Xenopus oocytes. Two substitutions, G9V and P37S, convert MeKTx11-1 to its natural analog MeKTx11-3 (α-KTx 1.17) having 15 times lower activity and reduced selectivity to KV1.2. We produced MeKTx11-1 and MeKTx11-3 as well as their mutants MeKTx11-1(G9V) and MeKTx11-1(P37S) recombinantly and demonstrated that point mutations provide an intermediate effect on selectivity. Key structural elements that explain MeKTx11-1 specificity were identified by molecular modeling of the toxin-channel complexes. Confirming our molecular modeling predictions, site-directed transfer of these elements from the pore region of KV1.2 to KV1.3 resulted in the enhanced sensitivity of mutant KV1.3 channels to MeKTx11-1. We conclude that MeKTx11-1 may be used as a selective tool in neurobiology.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neuropharmacology - Volume 143, December 2018, Pages 228-238
Journal: Neuropharmacology - Volume 143, December 2018, Pages 228-238
نویسندگان
Alexey I. Kuzmenkov, Oksana V. Nekrasova, Steve Peigneur, Valentin M. Tabakmakher, Andrei M. Gigolaev, Arkady F. Fradkov, Kseniya S. Kudryashova, Anton O. Chugunov, Roman G. Efremov, Jan Tytgat, Alexey V. Feofanov, Alexander A. Vassilevski,