Structure of murine angiogenin: features of the substrate- and cell-binding regions and prospects for inhibitor-binding studies.
Structure of murine angiogenin: features of the substrate- and cell-binding regions and prospects for inhibitor-binding studies.
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DOI：
10.1107/s0907444905029616
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发表时间：
2005-12
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血管生成素是胰腺核糖核酸酶超家族的一个不寻常的成员，它诱导血管形成，是一个有前途的抗癌靶点。用X射线晶体学方法测定了小鼠血管生成素（mAng）的三维结构。呈现两种结构，一种是与硫酸根离子的复合物（1.5 μ m-分辨率），另一种是与磷酸根离子的复合物（1.6 μ m-分辨率）。形成推定的B1、P1和B2亚位点的残基占据与它们的hAng对应物相似的位置，并且可能发挥相似的作用。阴离子占据P1亚位点，硫酸盐结合常规和磷酸盐采用两个方向，其中一个是新的。B1亚位点被Glu 116和Phe 119阻塞，后者假设比其hAng对应物侵入性更小的位置。C-末端片段和蛋白质主体之间的疏水相互作用比hAng更广泛，并且可能是鼠蛋白的较低酶活性的基础。在其他地方，H3-B2环的结构支持这样的观点，即hAng Asn 61直接与细胞表面分子相互作用，而不仅仅稳定hAng结构的相邻区域。mAng晶体似乎为小分子抑制剂提供了一条通往活性位点的明确途径，甚至可以承受C-末端片段的重新定向，从而提供通往隐蔽B1亚位点的途径。这些特征代表了相对于结晶hAng和bAng的相当大的优点。
Angiogenin is an unusual member of the pancreatic ribonuclease superfamily that induces blood vessel formation and is a promising anticancer target. The three-dimensional structure of murine angiogenin (mAng) has been determined by X-ray crystallography. Two structures are presented, one a complex with sulphate ions (1.5 Å-resolution) and the other with phosphate ions (1.6 Å-resolution). Residues forming the putative B1, P1 and B2 subsites occupy positions similar to their hAng counterparts and are likely to play similar roles. The anions occupy the P1 subsite, sulphate binding conventionally and phosphate adopting two orientations, one of which is novel. The B1 subsite is obstructed by Glu116 and Phe119, with the latter assuming a less invasive position than its hAng counterpart. Hydrophobic interactions between the C-terminal segment and the main body of the protein are more extensive than in hAng and may underly the lower enzymatic activity of the murine protein. Elsewhere, the structure of the H3–B2 loop supports the view that hAng Asn61 interacts directly with cell surface molecules and does not merely stabilize adjacent regions of the hAng structure. mAng crystals appear to offer small-molecule inhibitors a clear route to the active site and may even withstand a reorientation of the C-terminal segment that provides access to the cryptic B1 subsite. These features represent considerable advantages over crystalline hAng and bAng.