Crystal structure of the FTO protein reveals basis for its substrate specificity

Zhifu Han, Tianhui Niu, Junbiao Chang, Xiaoguang Lei, Mingyan Zhao, Qiang Wang, Wei Cheng, Jinjing Wang, Yi Feng and Jijie Chai ()
Additional contact information
Zhifu Han: National Institute of Biological Sciences, No. 7 Science Park Road, Beijing 102206, China
Tianhui Niu: National Institute of Biological Sciences, No. 7 Science Park Road, Beijing 102206, China
Junbiao Chang: Zhengzhou University
Xiaoguang Lei: National Institute of Biological Sciences, No. 7 Science Park Road, Beijing 102206, China
Mingyan Zhao: National Institute of Biological Sciences, No. 7 Science Park Road, Beijing 102206, China
Qiang Wang: Zhengzhou University
Wei Cheng: National Institute of Biological Sciences, No. 7 Science Park Road, Beijing 102206, China
Jinjing Wang: National Institute of Biological Sciences, No. 7 Science Park Road, Beijing 102206, China
Yi Feng: National Institute of Biological Sciences, No. 7 Science Park Road, Beijing 102206, China
Jijie Chai: National Institute of Biological Sciences, No. 7 Science Park Road, Beijing 102206, China

Nature, 2010, vol. 464, issue 7292, 1205-1209

Abstract: How FTO targets obesity The fat mass and obesity-associated (FTO) gene is associated with increased body weight and obesity risk. FTO protein is a DNA/RNA demethylase, and mice lacking it are abnormally lean. Now the crystal structure of human FTO in complex with the mononucleotide 3-meT has been determined. The structure reveals a novel mechanism by which the protein can discriminate between single- and double-stranded DNA. In addition, biochemical assays show that the C-terminal domain of FTO, previously of unknown function, is required for FTO catalytic activity via interactions with the N-terminal catalytic domain. These results provide a structural basis for understanding FTO substrate specificity, and serve as a foundation for the rational design of FTO inhibitors as potential anti-obesity agents.

Date: 2010
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DOI: 10.1038/nature08921

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