Structure-based activity prediction for an enzyme of unknown function
Structure-based activity prediction for an enzyme of unknown function
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DOI：
10.1038/nature05981
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发表时间：
2007-08-16
期刊：
影响因子：
64.8
通讯作者：
Raushel, Frank M.
中科院分区：
文献类型：
--
作者：
Hermann, Johannes C.;Marti-Arbona, Ricardo;Raushel, Frank M.
随着许多基因组的测序，生物学中的一个紧迫挑战是预测这些基因编码的蛋白质的功能。当蛋白质与已知活性的其他蛋白质无关时，生物信息学对功能的推断就成了问题。因此，直接询问蛋白质结构的功能将是有用的。在这里，我们通过对接数千种候选代谢物的高能中间形式来预测来自Thermotoga maritima的未知活性酶Tm0936的功能。对接的黑名单上主要是腺嘌呤类似物，它们似乎经历了C6脱氨基反应。以5-甲硫基腺苷和S-腺苷同型半胱氨酸为底物，其中3个具有较高的催化速率常数(10(5)M~(-1)S~(-1))。测定了Tm0936与SAH脱氨基产物S-肌苷同型半胱氨酸形成的配合物的X-射线晶体结构，与预测结构吻合较好。去氨基产物可以通过先前未知的SAH降解途径被毛滴虫进一步代谢。基于结构的对接与高能形式的潜在底物可能是一个有用的工具来诠释酶的功能。
With many genomes sequenced, a pressing challenge in biology is predicting the function of the proteins that the genes encode. When proteins are unrelated to others of known activity, bioinformatics inference for function becomes problematic. It would thus be useful to interrogate protein structures for function directly. Here, we predict the function of an enzyme of unknown activity, Tm0936 from Thermotoga maritima, by docking high- energy intermediate forms of thousands of candidate metabolites. The docking hit list was dominated by adenine analogues, which appeared to undergo C6- deamination. Four of these, including 5- methylthioadenosine and S- adenosylhomocysteine ( SAH), were tested as substrates, and three had substantial catalytic rate constants ( 10(5) M-1 s(-1)). The X- ray crystal structure of the complex between Tm0936 and the product resulting from the deamination of SAH, S- inosylhomocysteine, was determined, and it corresponded closely to the predicted structure. The deaminated products can be further metabolized by T. maritima in a previously uncharacterized SAH degradation pathway. Structure- based docking with high- energy forms of potential substrates may be a useful tool to annotate enzymes for function.