2wh9 | pdb_00002wh9
Solution structure of GxTX-1E
Structural highlights
FunctionTXG1E_CHIGU Gating modifier of Kv2.1/KCNB1 (IC(50)=5.1 nM), Kv2.2/KCNB2 and Kv4.3/KCND3 channels (IC(50)=39 nM). Acts by shifting the channel activation to more depolarized potentials by stabilizing the resting conformation of the voltage sensor. It completely inhibits opening of the Kv2.1/KCNB1 channel at negative membrane voltages and dramatically shifts channel activation to positive voltages. May act by partitioning into lipid membranes and then by binding the voltage sensor paddle of the channel from a place within the membrane.[1] [2] [3] Publication Abstract from PubMedGxTX-1E is a neurotoxin recently isolated from Plesiophrictus guangxiensis venom that inhibits the Kv2.1 channel in pancreatic beta-cells. The sequence of the toxin is related to those of previously studied tarantula toxins that interact with the voltage sensors in Kv channels, and GxTX-1E interacts with the Kv2.1 channel with unusually high affinity, making it particularly useful for structural and mechanistic studies. Here we determined the three-dimensional solution structure of GxTX-1E using NMR spectroscopy and compared it to that of several related tarantula toxins. The molecular structure of GxTX-1E is similar to those of tarantula toxins that target voltage sensors in Kv channels in that it contains an ICK motif, composed of beta-strands, and contains a prominent cluster of solvent-exposed hydrophobic residues surrounded by polar residues. When compared with the structure of SGTx1, a toxin for which mutagenesis data are available, the residue compositions of the two toxins are distinct in regions that are critical for activity, suggesting that their modes of binding to voltage sensors may be different. Interestingly, the structural architecture of GxTX-1E is also similar to that of JZTX-III, a tarantula toxin that interacts with Kv2.1 with low affinity. The most striking structural differences between GxTX-1E and JZTX-III are found in the orientation between the first and second cysteine loops and the C-terminal region of the toxins, suggesting that these regions of GxTX-1E are responsible for its high affinity. Solution Structure of GxTX-1E, a High-Affinity Tarantula Toxin Interacting with Voltage Sensors in Kv2.1 Potassium Channels .,Lee S, Milescu M, Jung HH, Lee JY, Bae CH, Lee CW, Kim HH, Swartz KJ, Kim JI Biochemistry. 2010 Jun 7. PMID:20509680[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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