| Project/Area Number |
11307053
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Physical pharmacy
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| Research Institution | The University of Tokyo |
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Principal Investigator |
SHIMADA Ichio Graduate School of Pharmaceutical sciences, The University of Tokyo, Professor, 大学院・薬学研究科, 教授 (70196476)
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| Co-Investigator(Kenkyū-buntansha) |
加藤 晃一 名古屋市立大学, 薬学部, 教授 (20211849)
高橋 栄夫 東京大学, 大学院・薬学系研究科, 助手 (60265717)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥39,650,000 (Direct Cost: ¥37,100,000、Indirect Cost: ¥2,550,000)
Fiscal Year 2001: ¥11,050,000 (Direct Cost: ¥8,500,000、Indirect Cost: ¥2,550,000)
Fiscal Year 2000: ¥8,500,000 (Direct Cost: ¥8,500,000)
Fiscal Year 1999: ¥20,100,000 (Direct Cost: ¥20,100,000)
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| Keywords | Nuclear Magnetic Resonance / Structural Biology / Ion Channel / Gating Modifier / Drug Design / NMR / 相互作用 / ゲーディングモディファイアー / 立体構造 / ブロッカー |
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| Research Abstract |
ω-Grammotoxin SlA (GrTx) is a 36 amino acid residue protein toxin from spider venom that inhibits P/Q and N type voltage-gated Ca^<2+> channels by modifying voltage-dependent gating. We determined the three-dimensional structure of GrTx using NMR spectroscopy. The toxin adopts an 'inhibitor cystine knot' motif composed of two β-strands (Leu19 - Cys21 and Cys30 - Trp32) and a β-bulge (Trp6, Gry7 - Cys30) with a +2x, 1 topology, which are connected by four chain reversals. Although GrTx was originally identified as an inhibitor of voltage-gated Ca^<2+> channel, it also binds to K^+ channels with lower affinity. A similar cross-reaction was observed for HaTx, which binds to the voltage-sensing domains of K^+ and Ca^<2+> channels with different affinities. A detailed comparison of the GrTx and HaTx structures identifies a well-conserved face containing a large hydrophobic patch surrounded by positively charged residues. The slight differences in the surface shape, which result from the orientation of the surface aromatic residues and/or the distribution of the charged residues, may explain differences in the binding affinity of these gating modifiers with different voltage-gated ion channels.
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