Biological Assembly Image for 3LFM (图片来源：PDB)
专题：Nature系列
许多科学研究表明，基因与肥胖存在千丝万缕的联系。一种被形象地称为“肥胖基因”的FTO基因有可能是导致肥胖的“罪魁祸首”。近日，北京生命科学研究所和天津大学科研人员联手在国际上第一次解析出了FTO基因表达蛋白质的晶体结构，并进一步证明了该蛋白质是一类脱氧核糖核酸（DNA）去甲基化酶。该开创性的研究成果在8日出版的国际著名学术期刊《自然》杂志上发表。
当前，肥胖已成为人类面临的一个严重的公共健康问题。目前我国肥胖者已超过9000万名，超重者高达2亿名。专家预测，未来10年，中国肥胖人群将会超过2亿。肥胖不但会导致糖尿病、高血压、癌症等诸多疾病，还会使人早逝。有数据表明，肥胖者早逝的危险是非肥胖者的1.3―2倍。科学研究显示，FTO基因会抑制新陈代谢，降低能量消耗效率，从而导致肥胖。因此，对于FTO基因及其表达的蛋白质的研究已经成为国际上生物医学领域的热点。
目前，北京生命科学研究所柴继杰博士实验室与天津大学药物化学系副教授雷晓光博士实验室正在进一步紧密合作，基于此项研究，通过计算机辅助药物设计和高通量药物筛选方法，寻找有效的小分子化合物，进而研制出具有我国自主知识产权、创新型治疗肥胖症的药物。专家认为，这是一项具有国际领先水平的开创性成果，为我国治疗肥胖症的创新型药物研发奠定坚实基础。
原文出处：
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.
