A possible molecular mechanism of hanatoxin binding‐modified gating in voltage‐gated K⁺‐channels

Abstract

While S4 is known as the voltage sensor in voltage-gated potassium channels, the carboxyl terminus of S3 (S3C) is of particular interest concerning the site for gating modifier toxins like hanatoxin. The thus derived helical secondary structural arrangement for S3C, as well as its surrounding environment, has since been intensively and vigorously debated. Our previous structural analysis based on molecular simulation has provided sufficient information to describe reasonable docking conformation and further experimental designs (Lou et al., 2002. J. Mol. Recognit. 15: 175-179). However, if one only relies on such information, more advanced structure-functional interpretations for the roles S3C may play in the modification of gating behavior upon toxin binding will remain unknown. In order to have better understanding of the molecular details regarding this issue, we have performed the docking simulation with the S3C sequence from the hanatoxin-insensitive K+-channel, shaker, and analyzed the conformational changes resulting from such docking. Compared with other functional data from previous studies with respect to the proximity of the S3-S4 linker region, we suggested a significant movement of drk1 S3C, but not shaker S3C, in the direction presumably towards S4, which was comprehended as a possible factor interfering with S4 translocation during drk1 gating in the presence of toxin. In combination with the discussions for structural roles of the length of the S3-S4 linker, a possible molecular mechanism to illustrate the hanatoxin binding-modified gating is proposed.

Functional and structural characterization of PKA-mediated pHi gating of ROMK1 channels

“…Homology modeling was performed following previously described procedures [26][27][28]. Briefly, the residues of the ROMK1 channel chosen according to the results of GCG paired sequence alignment were superimposed onto the structure coordinates of the C a atoms of the corresponding SCRs from the template channel structure (PDB ID: 1P7B).…”

Lipid Bilayer Deformation and the Free Energy of Interaction of a Kv Channel Gating-Modifier Toxin

“…They are activated by a change in transmembrane (TM) voltage (from polarized to depolarized), which results in a switch from a functionally closed to an open state (''gating''). Gating-modifier toxins are of particular interest because they can be used to probe the structure and orientation of the voltage sensor (VS), i.e., the domain of Kv channels that moves in response to changes in TM voltage (5,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). For example, VSTx1 has been shown to inhibit the archaebacterial channel KvAP by binding to the VSs, thus stabilizing the channel in an open state (11,12,24,26,29).…”

Structural basis for the inhibition of voltage-dependent K+ channel by gating modifier toxin

“…Pore blocking toxins target the extracellular side of the pore domain, and the structural basis, on which the toxins physically occlude the pore, has been revealed 12 13 14 15 . On the other hand, gating modifier toxins bind to VSD, and are assumed to alter the conformation and energetics of voltage-dependence of VSD 16 17 18 whereas the structural basis for the inhibition has not been fully elucidated.…”