1px9
From Proteopedia
Solution structure of the native CnErg1 Ergtoxin, a highly specific inhibitor of HERG channel
Structural highlights
FunctionKGX11_CENNO Blocks human and rat Kv11.1/KCNH2/ERG1 and Kv11.3/KCNH7/ERG3, as well as rat (but not human) Kv11.2/KCNH6/ERG2 (PubMed:11755529, PubMed:11864985, PubMed:16497878, PubMed:17369411, PubMed:20600425) by binding to channel outer vestibule (S5P domain) with a 1:1 stoichiometry (PubMed:11755529, PubMed:11864985, PubMed:17369411, PubMed:20600425). Inhibition data are the following: hERG1 (reversible, IC(50)~7 nM) (PubMed:11755529, PubMed:11864985, PubMed:16497878, PubMed:17369411, PubMed:20600425), rERG1 (reversible, Kd=6.8 nM) (PubMed:16497878), rERG2 (irreversible, Kd=2.8 nM) (PubMed:16497878), hERG3 (irreversible, Kd=4.05 nM) (PubMed:16497878) and rERG3 (reversible, Kd=38.1 nM) (PubMed:16497878) potassium channels. The toxin potency is not affected by elevating potassium ion concentration from 2 to 98 mM (PubMed:11864985). This toxin only blocks channels in a closed state (PubMed:12860380). At high toxin concentrations, block of Kv11.1/KCNH2/ERG1 macroscopic current is incomplete (93.5%). This suggests a kinetic mechanism model with two different states of toxin-channel binding (T+C=TC*=TC; in the TC* state, the toxin binds the channel but does not occlude the pore, whereas in the TC state the toxin binds and occludes the pore). In this model, incomplete block is explained by the relatively fast dissociation rate from the blocked channel conformation (TC) relative to the rate of conversion of the toxin-channel encounter complex (TC*) to the blocked channel conformation (TC) (PubMed:17369411).[1] [2] [3] [4] [5] [6] [7] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe gamma-KTx-type scorpion toxins specific for K+ channels were found to interact with ERG channels on the turret region, while alpha-KTx3.2 Agitoxin-2 binds to the pore region of the Shaker K+ channel, and alpha-KTx5.3 BmP05 binds to the intermediate region of the small-conductance calcium-activated K-channel (SK(Ca)). In order to explore the critical residues for gamma-KTx binding, we determined the NMR structure of native gamma-KTx1.1 (CnErg1), a 42 amino acid residues scorpion toxin isolated from the venom of the Mexican scorpion Centruroides noxius Hoffmann, and we used computational evolutionary trace (ET) analysis to predict possible structural and functional features of interacting surfaces. The 1H-NMR three-dimensional solution structure of native ergtoxin (CnErg1) was solved using a total of 452 distance constraints, 13 3J(NH-Halpha) and 10 hydrogen bonds. The structure is characterized by 2 segments of alpha-helices and a triple-stranded antiparallel beta-sheet stabilized by 4 disulfide bridges. The ET and structural analysis provided indication of the presence of two important amino acid residue clusters, one hydrophobic and the other hydrophilic, that should be involved in the surface contact between the toxin and the channel. Some features of the proposed interacting surface are discussed. Exploring structural features of the interaction between the scorpion toxinCnErg1 and ERG K+ channels.,Frenal K, Xu CQ, Wolff N, Wecker K, Gurrola GB, Zhu SY, Chi CW, Possani LD, Tytgat J, Delepierre M Proteins. 2004 Aug 1;56(2):367-75. PMID:15211519[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations No citations found See AlsoReferences
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