Crystal structure of the FTO protein reveals basis for its substrate specificity
Crystal structure of the FTO protein reveals basis for its substrate specificity
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DOI：
10.1038/nature08921
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发表时间：
2010-04-22
期刊：
影响因子：
64.8
通讯作者：
Chai, Jijie
中科院分区：
文献类型：
--
作者：
Han, Zhifu;Niu, Tianhui;Chai, Jijie
最近的研究（1-5）已经明确地将脂肪量和肥胖相关（FTO）基因与肥胖的风险联系起来。体外FTO蛋白是一种AlkB样DNA/RNA脱甲基酶，对单链DNA中的3-甲基胸苷（3-meT）或单链RNA中的3-甲基尿嘧啶（3-meU）具有强烈偏好（6-8）。在这里，我们报告的晶体结构的FTO在复杂的monopoltide 3-meT。FTO包含氨基端AlkB样结构域和具有新折叠的羧基端结构域。生化分析表明，这两个结构域相互作用，这是所需的FTO催化活性。与其他AlkB成员的结构相比，FTO具有额外的环，覆盖保守的卷曲基序的一侧。结构比较显示，该环选择性地与DNA双链体的未甲基化链竞争结合FTO，表明其在针对双链核酸的FTO选择中具有重要作用。FTO区分3-meT或3-meU与其他核苷酸的能力是由其与3-meT或3-meU中的两个羰基氧原子的氢键相互作用赋予的。总之，这些结果为理解FTO底物特异性提供了结构基础，并为FTO抑制剂的合理设计奠定了基础。
Recent studies(1-5) 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 RNA(6-8). 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.