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

开发钠通道功能障碍疗法的结构研究

• 批准号: 09470493
• 负责人: KURODA Yoshihiro
• 金额: $ 8.58万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470493/
• 关键词: Sodium channel; Inactivation gate; Peptide; Local anesthetics; Dibucaine; Interaction; NMR spectrum; CD spectrum; ミセル; フォスファチジルセリン; リポソーム

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.

1.在生理条件下具有电荷的叔胺型局部麻醉剂与III-IV接头的疏水基序IMF中的苯丙氨酸残基疏水相互作用，并且还与位于IMF基序之前和之后的酸性氨基酸残基静电相互作用。在与上述类似的条件下，苯并咪唑与叔胺型局部麻醉剂一样位于极性头基团区域，但不能与III-IV连接体相互作用。IMF基序周围的结构一般为α-螺旋。IMF基序周围的结构由IMF中的异亮氨酸和位于IMF残基之后的苏氨酸之间的氢键控制。五肽KIFMK与III-IV接头特异性相互作用，并稳定IMF基序结构周围的α-螺旋结构。作为其中苏氨酸突变为甲硫氨酸的先天性副肌强直（PMC）的治疗剂，认为可以稳定野生型钠中IFMT基序形成的α-螺旋结构的分子可以是良好的药物。

项目成果

Kuroda,Yoshihiro: "H-NMR and Circular Dichroism Spectroscopic Studies on Changes in Secondary Structures of the Sodium Channel Inactivation Gate Peptides as Caused by the Pentapeptide KIFMK"Biophysical Journal. 77. 1363-1373 (1999)

Kuroda, Yoshihiro：“H-NMR 和圆二色性光谱研究五肽 KIFMK 引起的钠通道失活门肽二级结构的变化”生物物理学杂志。

YOSHIHIRO Kuroda: "^1H-NMR and Circular Dichroism Spectroscopic Studies on Changes in Secondary Structures of the Sodium Channel Inactivation Gate Peptides as Caused by the Pentapeptide KIFMK"Biophysical Journal. 77. 1363-1373 (1999)

YOSHIHIRO Kuroda：“^1H-NMR 和圆二色性光谱研究五肽 KIFMK 引起的钠通道失活门肽二级结构的变化”生物物理学杂志。

Yoshihiro Kuroda: "ィイD11ィエD1H-NMR and circular dichroism spectroscopic studies on changes in secondary structures of the sodium channel in activation gate peptides as ca us ed by the pentapep tide KIFMK"Biophysical Journal. 77. 1363-1373 (1999)

Yoshihiro Kuroda：“由五肽 KIFMK 引起的激活门肽中钠通道二级结构变化的 D11D1H-NMR 和圆二色性光谱研究”生物物理学杂志 77. 1363-1373 (1999)。