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首页> 外文期刊>Journal of Molecular Biology >Three-dimensional structure of a human pancreatic ribonuclease variant, a step forward in the design of cytotoxic ribonucleases
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Three-dimensional structure of a human pancreatic ribonuclease variant, a step forward in the design of cytotoxic ribonucleases

机译：人胰腺核糖核酸酶变体的三维结构，细胞毒性核糖核酸酶设计的新进展

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摘要

We have determined the crystal structure of a human pancreatic ribonuclease or RNase 1 variant at 1.65 Angstrom resolution. Five residues in the N-terminal region were substituted by the corresponding amino acids of the bovine seminal RNase. in addition, a Pro to Ser mutation was present at position 50. The substitution of part of the N terminus has been critical both in improving the expression of this enzyme as a recombinant protein and in achieving its crystallisation. The determination of the crystal structure revealed the characteristic RNase fold including a V-shaped beta -sheet and three alpha -helices. It differs from its bovine RNase orthologue mainly in the loop regions. The active-site cleft shows a similar architecture to that of its bovine counterpart, with the essential residues occupying equivalent positions. In the present structure, however, His119 is displaced as it is in the structure of RNase A at high pH. An interaction model of human ribonuclease with the ribonuclease inhibitor, together with inhibition assays, indicate that, in contrast to RNase A, the modification of the loop beta4 beta5 is not enough to avoid inhibition. This study represents the first crystallographic approach to the human enzyme, and should constitute an invaluable tool for the design of ribonudease variants with acquired cytotoxic properties. (C) 2000 Academic Press. [References: 56]
机译：我们已经确定了人类胰腺核糖核酸酶或RNase 1变异体的晶体结构，分辨率为1.65埃。 N-末端区域中的五个残基被牛精浆RNase的相应氨基酸取代。此外，Pro到Ser的突变出现在第50位。N末端部分的取代对于改善这种酶作为重组蛋白的表达以及实现其结晶都至关重要。晶体结构的确定揭示了特征性RNase折叠，包括V形β-折叠和三个α-螺旋。它与牛RNase直向同源物的主要区别在于环区。活性位点裂口与其牛对应位点的结构相似，基本残基占据相同的位置。然而，在本结构中，His119在高pH下原样在RNase A的结构中被置换。人核糖核酸酶与核糖核酸酶抑制剂的相互作用模型以及抑制试验表明，与RNase A相比，环beta4 beta5的修饰不足以避免抑制。这项研究代表了人类酶的第一种晶体学方法，应该成为设计具有获得的细胞毒性的核糖核酸酶变体的宝贵工具。 （C）2000学术出版社。 [参考：56]

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