生物谷報(bào)道：如果一種新發(fā)現(xiàn)的蛋白與已知的酶相似時(shí),，科學(xué)家們常常據(jù)此來(lái)推斷未知酶的功能,，否則，單從結(jié)構(gòu)—功能關(guān)系是非常難以判斷未知酶的功能的,。
現(xiàn)在,，Johannes Hermann等人利用一種變通的分子對(duì)接方法（一種用來(lái)尋找潛在藥物的計(jì)算機(jī)輔助的模擬方法），設(shè)計(jì)出一種根據(jù)結(jié)構(gòu)來(lái)預(yù)測(cè)某種具有未知活性的酶的功能的方法,。試驗(yàn)用的酶是Tm0936,，來(lái)自極端喜熱的Thermotoga maritima。對(duì)接實(shí)驗(yàn)預(yù)測(cè),，它將使5-甲硫腺苷（﹡）和S-腺苷甲硫氨酸（﹡﹡）去胺化,；這一點(diǎn)已從與反應(yīng)產(chǎn)物相結(jié)合的該蛋白的X-射線晶體結(jié)構(gòu)上得到了證實(shí)。這種酶沒(méi)有與已知的腺苷胺化酶具有明顯相似的序列,，甚至它所參與的通道也似乎是新穎的,。如果這一新方法也適用于其他酶，那么它很可能成為一種有力工具,，來(lái)確定關(guān)鍵的酶在體內(nèi)是如何發(fā)揮作用的,。
原始出處:
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: [email protected]).
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.
