Structural investiga tions for developing therapeutics of functional disorders due to the sodium channel

1.在生理条件下带电荷的叔胺类局麻药与III-IV连接子疏水基序IMF中的苯丙氨酸残基发生疏水作用，并与IMF基序前后的酸性氨基酸残基发生静电相互作用。在与上述相似的条件下，苯佐卡因与叔胺类局域芳烃的情况一样位于极头基团区域，但不能与III-IV接头相互作用。围绕国际货币基金组织主题的结构通常是α-螺旋的。IMF基序周围的结构是由IMF中的异亮氨酸和苏氨酸之间的氢键控制的，苏氨酸在IMF残存后占据一席之地。五肽KIFMK能与If基序的III-IV连接子特异地相互作用，稳定IMF基序周围的α-螺旋结构。作为苏氨酸突变为蛋氨酸的副肌张力综合征的治疗药物，能够稳定野生型钠中IFMT基序形成的α-螺旋结构的分子被认为是一种很好的药物。

1. The tertiary amine type local anesthetics which possess a charge under physiological conditions interact hydrophobically with the phenylalanine residue in the hydrophobic motif, IMF, of the III-IV linker and also electrostatically with the acidic amino acid residues which locate before and after the IMF motif.2. At a similar condition as above, benzocaine locates at a polarhead-group region as in the case of the tertiary amine type local anes the tics, but cannot interact with the III-IV linker.3. The structure at around the IMF motifis generally α-helical. The structure at around the IMF motifis controlled by a hydrogen bonding between the isoleucine in the IMF and the threonine which take a position just after the IMF residues.4. A pentapeptide KIFMK interacts specifically with the III-IV linker and stabilizes the α-helical structure at around the structure of the IMF motif.As a therapeutic for paramyotonia congenita (PMC), in which the threonine is mutated into methionine, it is considered that a molecule which can stabilize the α-helical structure formed by the IFMT motifin the wild type sodium can be a good drug.