Nature封面：根据结构来预测未知酶功能的新方法

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Nature封面：根据结构来预测未知酶功能的新方法 如果一种新发现的蛋白与已知的酶相似时，科学家们常常据此来推断未知酶的功能，否则，单从结构—功能关系是非常难以判断未知酶的功能的。现在，JohannesHermann等人利用一种变通的分子对接方法（一种用来寻找潜在药物的计算机辅助的模拟方法），设计出一种根据结构来预测某种具有未知活性的酶的功能的方法。试验用的酶是Tm0936，来自极端喜热的Thermotogamaritima。对接实验预测，它将使5
  生物谷报道：如果一种新发现的蛋白与已知的酶相似时，科学家们常常据此来推断未知酶的功能，否则，单从结构—功能关系是非常难以判断未知酶的功能的。
  现在，Johannes Hermann等人利用一种变通的分子对接方法（一种用来寻找潜在药物的计算机辅助的模拟方法），设计出一种根据结构来预测某种具有未知活性的酶的功能的方法。试验用的酶是Tm0936，来自极端喜热的Thermotoga maritima。对接实验预测，它将使5-甲硫腺苷（﹡）和S-腺苷甲硫氨酸（﹡﹡）去胺化；这一点已从与反应产物相结合的该蛋白的X-射线晶体结构上得到了证实。这种酶没有与已知的腺苷胺化酶具有明显相似的序列，甚至它所参与的通道也似乎是新颖的。如果这一新方法也适用于其他酶，那么它很可能成为一种有力工具，来确定关键的酶在体内是如何发挥作用的。
原始出处:

Nature 448, 775-779 (16 August 2007) | doi:10.1038/nature05981; Received 24 January 2007; Accepted 7 June 2007; Published online 1 July 2007
Structure-based activity prediction for an enzyme of unknown function
Johannes C. Hermann1, Ricardo Marti-Arbona2, Alexander A. Fedorov3, Elena Fedorov3, Steven C. Almo3, Brian K. Shoichet1 & Frank M. Raushel2
Department of Pharmaceutical Chemistry, University of California, San Francisco, MC 2550 1700 4th Street, San Francisco, California 94158-2330, USA
Department of Chemistry, P.O. Box 30012, Texas A&M University, College Station, Texas 77842-3012, USA
Department of Biochemistry, Albert Einstein College of Medicine, Ullmann Building, Room 411, 1300 Morris Park Avenue, Bronx, New York 10461, USA
Correspondence to: Brian K. Shoichet1 Correspondence and requests for materials related to docking should be addressed to B.K.S. (Email: shoichet@cgl.ucsf.edu).
Abstract
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 (105 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.