Structure of Sonic Hedgehog protein in complex with zinc(II) and magnesium(II) reveals ion-coordination plasticity relevant to peptide drug design.
Structure of Sonic Hedgehog protein in complex with zinc(II) and magnesium(II) reveals ion-coordination plasticity relevant to peptide drug design.
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Sonic Hedgehog 蛋白与锌 (II) 和镁 (II) 复合物的结构揭示了与肽药物设计相关的离子配位可塑性。
DOI：
10.1107/s2059798319012890
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Wedekind,Joseph
中科院分区：
文献类型：
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作者：
Bonn-Breach,Rachel;Gu,Yu;Jenkins,Jermaine;Fasan,Rudi;Wedekind,Joseph
Hedgehog信号通路是一种重要的细胞信号传导模式，与癌症肿瘤发生和发育障碍无前脑畸形有关，使其成为治疗设计的有吸引力的靶点。Sonic Hedgehog蛋白的N端结构域（Shh-N）是Hedgehog信号通路中的重要信号分子。在这个角色中，Shh-N通过利用含有一个或多个二价离子的界面与其同源膜受体Patched以及调节蛋白HHIP和CDO相互作用。在这里，人Shh-N的晶体结构以1.43 μ m的分辨率呈现，代表了这种蛋白质表征的里程碑。 结构表明，保守的Zn 2+结合位点采用非典型的八面体配位几何形状，而相邻的结合位点，通常由双核Ca 2+占据，已被取代由一个单一的八面体结合Mg 2+。这两个二价的网站相比，在以前的Shh-N结构，这表明了一个显着程度的可塑性的Shh-N蛋白在二价离子结合。在结晶介质中的高Mg 2+浓度的存在下，似乎已经影响了在两个金属离子结合位点的金属负载。这些观察结果具有技术和设计上的影响，专注于开发抑制剂，靶向Shh-N介导的蛋白质-蛋白质相互作用的努力。
The Hedgehog pathway is an essential cell-signaling paradigm implicated in cancer tumorigenesis and the developmental disorder holoprosencephaly, making it an attractive target for therapeutic design. The N-terminal domain of the Sonic Hedgehog protein (Shh-N) is the essential signaling molecule in the Hedgehog pathway. In this role Shh-N interacts with its cognate membrane receptor Patched, as well as the regulatory proteins HHIP and CDO, by utilizing interfaces harboring one or more divalent ions. Here, the crystal structure of human Shh-N is presented at 1.43 Å resolution, representing a landmark in the characterization of this protein. The structure reveals that the conserved Zn2+-binding site adopts an atypical octahedral coordination geometry, whereas an adjacent binding site, normally occupied by binuclear Ca2+, has been supplanted by a single octahedrally bound Mg2+. Both divalent sites are compared with those in previous Shh-N structures, which demonstrates a significant degree of plasticity of the Shh-N protein in terms of divalent ion binding. The presence of a high Mg2+ concentration in the crystallization medium appears to have influenced metal loading at both metal ion-binding sites. These observations have technical and design implications for efforts focused on the development of inhibitors that target Shh-N-mediated protein–protein interactions.