Altered subunit communication in subfamilies of trimeric dUTPases
Altered subunit communication in subfamilies of trimeric dUTPases
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DOI：
10.1006/bbrc.2000.3994
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发表时间：
2000-12-20
影响因子：
3.1
通讯作者：
Vértessy, BG
中科院分区：
文献类型：
--
作者：
Fiser, A;Vértessy, BG
dUTR酶在防止尿嘧啶掺入DNA中是必不可少的。针对这种新的化疗靶点的拮抗剂的设计需要鉴定酶的结构和机制中的物种特异性差异。这个任务现在接近通过比较可用的晶体结构的dUTPases从智人，大肠杆菌，和逆转录病毒。真核蛋白独特地显示极性和带电氨基酸残基参与三重亚基间相互作用。在细菌和逆转录病毒dUTPases中，三重相互作用主要是疏水性的。负责这种对比的残基在多序列比对中被映射到不同的位置，并且在不同的进化分支中特征性地保守。这种对比的一般特点是进一步加强了第二真核生物模型结构构建使用比较建模。对来自黑腹果蝇（Drosophila melanogaster）的dUTR cDNA进行鉴定、测序，并且编码多肽的模型结构显示出与人类结构相同的三重相互作用的极性氢键网络。结果允许三聚体dUTPases的两个亚家族之间的明显区别，其中改变的亚基通信可以解释催化循环中的功能差异。(C)北京大学出版社.
The enzyme dUTPase is essential in preventing uracil incorporation into DNA. Design of antagonists against this novel chemotherapeutic target requires identification of species-specific differences in the structure and mechanism of the enzyme. This task is now approached via comparisons of available crystallographic structures of dUTPases from Homo sapiens, Escherichia coli, and retroviruses. The eukaryotic protein uniquely displays polar and charged amino acid residues participating in threefold intersubunit interactions. In bacterial and retroviral dUTPases, threefold interactions are mainly hydrophobic. The residues responsible for this contrast are mapped in multiple sequence alignment to positions differently and characteristically conserved in distinct evolutionary branches. The general feature of this contrast is further strengthened by a second eukaryotic model structure constructed using comparative modeling. The dUTPase cDNA from Drosophila melanogaster was identified, sequenced, and the model structure of the encoded polypeptide displayed a polar hydrogen-bonding network of threefold interactions, identically to the human structure. Results allow clear distinction between two subfamilies of trimeric dUTPases where altered subunit communication may account for a functional difference in the catalytic cycle. (C) 2000 Academic Press.