Structural basis of binding and inhibition of novel tarantula toxins in mammalian voltage-dependent potassium channels.

摘要

Voltage-dependent potassium channel Kv2.1 is widely expressed in mammalian neurons and was suggested responsible for mediating the delayed rectifier (I(K)) currents. Further investigation of the central role of this channel requires the development of specific pharmacology, for instance, the utilization of spider venom toxins. Most of these toxins belong to the same structural family with a short peptide reticulated by disulfide bridges and share a similar mode of action. Hanatoxin 1 (HaTx1) from a Chilean tarantula was one of the earliest discussed tools regarding this and has been intensively applied to characterize the channel blocking not through the pore domain. Recently, more related novel toxins from African tarantulas such as heteroscordratoxins (HmTx) and stromatoxin 1 (ScTx1) were isolated and shown to act as gating modifiers such as HaTx on Kv2.1 channels with electrophysiological recordings. However, further interaction details are unavailable due to the lack of high-resolution structures of voltage-sensing domains in such mammalian Kv channels. Therefore, in the present study, we explored structural observation via molecular docking simulation between toxins and Kv2.1 channels based upon the solution structures of HaTx1 and a theoretical basis of an individual S3(C) helical channel fragment in combination with homology modeling for other novel toxins. Our results provide precise chemical details for the interactions between these tarantula toxins and channel, reasonably correlating the previously reported pharmacological properties to the three-dimensional structural interpretation. In addition, it is suggested that certain subtle structural variations on the interaction surface of toxins may discriminate between the related toxins with different affinities for Kv channels. Evolutionary links between spider peptide toxins and a "voltage sensor paddles" mechanism most recently found in the crystal structure of an archaebacterial K(+) channel, KvAP, are also delineated in this paper.