Biological Assembly Image for 3LFM (圖片來(lái)源：PDB)
專題：Nature系列
許多科學(xué)研究表明,，基因與肥胖存在千絲萬(wàn)縷的聯(lián)系。一種被形象地稱為“肥胖基因”的FTO基因有可能是導(dǎo)致肥胖的“罪魁禍?zhǔn)?rdquo;,。近日,，北京生命科學(xué)研究所和天津大學(xué)科研人員聯(lián)手在國(guó)際上第一次解析出了FTO基因表達(dá)蛋白質(zhì)的晶體結(jié)構(gòu),，并進(jìn)一步證明了該蛋白質(zhì)是一類脫氧核糖核酸（DNA）去甲基化酶。該開創(chuàng)性的研究成果在8日出版的國(guó)際著名學(xué)術(shù)期刊《自然》雜志上發(fā)表,。
當(dāng)前,，肥胖已成為人類面臨的一個(gè)嚴(yán)重的公共健康問(wèn)題。目前我國(guó)肥胖者已超過(guò)9000萬(wàn)名,，超重者高達(dá)2億名,。專家預(yù)測(cè)，未來(lái)10年,，中國(guó)肥胖人群將會(huì)超過(guò)2億,。肥胖不但會(huì)導(dǎo)致糖尿病、高血壓,、癌癥等諸多疾病,，還會(huì)使人早逝。有數(shù)據(jù)表明,，肥胖者早逝的危險(xiǎn)是非肥胖者的1.3—2倍,。科學(xué)研究顯示,，F(xiàn)TO基因會(huì)抑制新陳代謝,，降低能量消耗效率，從而導(dǎo)致肥胖,。因此,，對(duì)于FTO基因及其表達(dá)的蛋白質(zhì)的研究已經(jīng)成為國(guó)際上生物醫(yī)學(xué)領(lǐng)域的熱點(diǎn)。
目前,，北京生命科學(xué)研究所柴繼杰博士實(shí)驗(yàn)室與天津大學(xué)藥物化學(xué)系副教授雷曉光博士實(shí)驗(yàn)室正在進(jìn)一步緊密合作，基于此項(xiàng)研究,，通過(guò)計(jì)算機(jī)輔助藥物設(shè)計(jì)和高通量藥物篩選方法,，尋找有效的小分子化合物，進(jìn)而研制出具有我國(guó)自主知識(shí)產(chǎn)權(quán),、創(chuàng)新型治療肥胖癥的藥物,。專家認(rèn)為，這是一項(xiàng)具有國(guó)際領(lǐng)先水平的開創(chuàng)性成果,，為我國(guó)治療肥胖癥的創(chuàng)新型藥物研發(fā)奠定堅(jiān)實(shí)基礎(chǔ),。（生物谷Bioon.com）
延伸閱讀
Nature：HIV-1整合酶三維結(jié)構(gòu)
Cell：PSPs的結(jié)構(gòu)以及生化功能
Nature：甲酸（formate）通道蛋白FocA結(jié)構(gòu)
Genes & Development：人源蛋白質(zhì)三維結(jié)構(gòu)
PLoS One：冠狀病毒結(jié)構(gòu)研究
PNAS：解析C/D RNA蛋白質(zhì)復(fù)合物的晶體結(jié)構(gòu)
生物谷推薦原文出處：
Nature advance online publication 7 April 2010 | doi:10.1038/nature08921
Crystal structure of the FTO protein reveals basis for its substrate specificity
Zhifu Han1,6, Tianhui Niu1,2,6, Junbiao Chang3, Xiaoguang Lei1,4, Mingyan Zhao1, Qiang Wang3, Wei Cheng1, Jinjing Wang1, Yi Feng1 & Jijie Chai1,5
1 National Institute of Biological Sciences, No. 7 Science Park Road, Beijing 102206, China
2 College of Biological Sciences, China Agricultural University, Beijing 100094, China
3 Department of Chemistry, Zhengzhou University, Zhengzhou 450001, China
4 School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
5 Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China
6 These authors contributed equally to this work.
Recent studies1, 2, 3, 4, 5 have unequivocally associated the fat mass and obesity-associated (FTO) gene with the risk of obesity. In vitro FTO protein is an AlkB-like DNA/RNA demethylase with a strong preference for 3-methylthymidine (3-meT) in single-stranded DNA or 3-methyluracil (3-meU) in single-stranded RNA6, 7, 8. Here we report the crystal structure of FTO in complex with the mononucleotide 3-meT. FTO comprises an amino-terminal AlkB-like domain and a carboxy-terminal domain with a novel fold. Biochemical assays show that these two domains interact with each other, which is required for FTO catalytic activity. In contrast with the structures of other AlkB members, FTO possesses an extra loop covering one side of the conserved jelly-roll motif. Structural comparison shows that this loop selectively competes with the unmethylated strand of the DNA duplex for binding to FTO, suggesting that it has an important role in FTO selection against double-stranded nucleic acids. The ability of FTO to distinguish 3-meT or 3-meU from other nucleotides is conferred by its hydrogen-bonding interaction with the two carbonyl oxygen atoms in 3-meT or 3-meU. Taken together, these results provide a structural basis for understanding FTO substrate-specificity, and serve as a foundation for the rational design of FTO inhibitors.
