近日，美國(guó)和以色列科學(xué)家用計(jì)算機(jī)設(shè)計(jì)出一種含鋅酶,，可以對(duì)具有與神經(jīng)藥劑沙林類似結(jié)構(gòu)的分子進(jìn)行降解,，相關(guān)論文發(fā)表在《自然—化學(xué)生物學(xué)》（Nature Chemical Biology）上。
近年來(lái),，蛋白質(zhì)合理設(shè)計(jì)取得重要進(jìn)展,，科學(xué)家可以通過(guò)新蛋白質(zhì)折疊和新酶活性進(jìn)行蛋白質(zhì)測(cè)序。但是,，很少有人注意到將金屬與之相結(jié)合的嘗試,。而在該項(xiàng)研究中，這種加入金屬后得到的酶具有針對(duì)各種特殊反應(yīng)的催化能力,，從而極大地為蛋白質(zhì)設(shè)計(jì)中各種可能的反應(yīng)拓寬道路,。
David Baker和同事檢驗(yàn)了大量已知含鋅酶，從中篩選出12種形狀可被重新設(shè)計(jì)以便于研究的酶,。他們發(fā)現(xiàn),，其中一種酶具有分解有機(jī)磷分子的活性。通過(guò)進(jìn)一步設(shè)計(jì)并以新酶的晶體結(jié)構(gòu)為部分依據(jù),，研究小組成功得到了這種新型酶,。（生物谷Bioon.com）
doi:10.1038/nchembio.777
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Computational redesign of a mononuclear zinc metalloenzyme for organophosphate hydrolysis
Sagar D Khare, Yakov Kipnis, Per Jr Greisen, Ryo Takeuchi, Yacov Ashani, Moshe Goldsmith, Yifan Song, Jasmine L Gallaher, Israel Silman, Haim Leader, Joel L Sussman, Barry L Stoddard, Dan S Tawfik & David Baker
The ability to redesign enzymes to catalyze noncognate chemical transformations would have wide-ranging applications. We developed a computational method for repurposing the reactivity of metalloenzyme active site functional groups to catalyze new reactions. Using this method, we engineered a zinc-containing mouse adenosine deaminase to catalyze the hydrolysis of a model organophosphate with a catalytic efficiency (kcat/Km) of ～104 M?1 s?1 after directed evolution. In the high-resolution crystal structure of the enzyme, all but one of the designed residues adopt the designed conformation. The designed enzyme efficiently catalyzes the hydrolysis of the RP isomer of a coumarinyl analog of the nerve agent cyclosarin, and it shows marked substrate selectivity for coumarinyl leaving groups. Computational redesign of native enzyme active sites complements directed evolution methods and offers a general approach for exploring their untapped catalytic potential for new reactivities.
