Structural Basis of Binding and Inhibition of Novel Tarantula Toxins in Mammalian Voltage-Dependent Potassium Channels

Voltage-dependent potassium channel Kv2.1 is widely expressed in mammalian
neurons and was suggested responsible for mediating the delayed rectifier (IK)
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 like
heteroscordratoxins (HmTx) and stromatoxin 1 (ScTx1) were isolated and shown to
act as gating modifiers like 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 S3C 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 3-D 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.