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首页> 外文期刊>Biochemistry >Role of Asn-16 and Ser-19 in Anthopleurin B Binding.Implications for the Electrostatic Nature of Nav Site
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Role of Asn-16 and Ser-19 in Anthopleurin B Binding.Implications for the Electrostatic Nature of Nav Site

机译：Asn-16和Ser-19在花青素B结合中的作用。对导航位点的静电性质的影响

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摘要

Anthopleurin B (ApB) is a type 1 sea anemone toxin,which binds to voltage-sensitive sodium channels (Nav's),thereby delaying channel inactivation.Previous work from our laboratories has demonstrated that the structurally unconstrained region involving residues 8-17 of this polypeptide,designated the Arg-14 loop,is important for full toxin affinity (Seibert et al.,(2003) Biochemistry 42,14515).Within this region,important contributions are made by residues Arg-12 and Leu-18 (Gallagher and Blumenthal,(1994)J.Biol Chem.269,254; Dias-Kadambi et al.,(1996)J.Biol Chem.277,23828).Moreover,replacement of glycine residues found at positions 10 or 15 of the loop by alanine has been shown to have profound,isoform-selective effects on toxin-binding kinetics (Seibert et al.,(2003) Biochemistry 42,14515).To thoroughly understand the importance of this entire region,the work described here investigates the contribution of ApB residues Asn-16,Thr-17,and Ser-19 to toxin affinity and isoform selectivity.Our results demonstrate that residues within and proximal to the C terminus of the Arg-14 loop are important modulators of ApB affinity for Nav channels,indicating that the loop and channel site 3 are likely in close contact.A comparison of the effects of multiple replacements at each position reveals that Asn-16 and Ser-19 are involved in binding,whereas Thr-17 is not.The fact that anionic replacements for Asn-16 or Ser-19 are highly deleterious for toxin binding strongly suggests that site 3 contains either formal anionic residues or regions of high electron density,which could be formed by aromatic clusters.These data represent the first indication of the presence of such residues or regions within Nav site 3.
机译：花青素B（ApB）是一种1型海葵毒素，与电压敏感的钠通道（Nav's）结合，从而延迟了通道失活。我们实验室的先前工作表明，该多肽的结构不受限制的区域涉及第8-17位残基标记为Arg-14的环对于充分的毒素亲和力很重要（Seibert等，（2003）Biochemistry 42,14515）。在该区域内，残基Arg-12和Leu-18（Gallagher和Blumenthal）发挥了重要作用。 ，（1994）J.Biol Chem.269,254; Dias-Kadambi等人，（1996）J.Biol Chem.277,23828）。此外，已经用丙氨酸代替了在环的10或15位上发现的甘氨酸残基。证明对毒素结合动力学具有深远的，同工型的选择性作用（Seibert et al。，（2003）Biochemistry 42,14515）。为了透彻地了解整个区域的重要性，本文所述的工作调查了ApB残基Asn的贡献-16，Thr-17和Ser-19对毒素的亲和力和同工型选择性我们的研究结果表明，Arg-14环C末端内及其附近的残基是Nav通道ApB亲和力的重要调节剂，表明该环和通道位点3可能紧密接触。每个位置的置换都表明Asn-16和Ser-19参与了结合，而Thr-17则不参与。Asn-16或Ser-19的阴离子置换对毒素的结合非常有害，这一事实强烈表明位点3含有可能是由芳族簇形成的形式化阴离子残基或高电子密度区域，这些数据代表了Nav站点3中存在此类残基或区域的第一个迹象。

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