4ie6
From Proteopedia
Crystal structure of the human fat mass and obesity associated protein (FTO) in complex with N-[(1-chloro-4-hydroxyisoquinolin-3-yl)carbonyl]glycine (IOX3/UN9)
Structural highlights
Disease[FTO_HUMAN] Defects in FTO are the cause of growth retardation developmental delay coarse facies and early death (GDFD) [MIM:612938]. A severe polymalformation syndrome characterized by postnatal growth retardation, microcephaly, severe psychomotor delay, functional brain deficits and characteristic facial dysmorphism. In some patients, structural brain malformations, cardiac defects, genital anomalies, and cleft palate are observed. Early death occurs by the age of 3 years.[1] Function[FTO_HUMAN] Dioxygenase that repairs alkylated DNA and RNA by oxidative demethylation. Has highest activity towards single-stranded RNA containing 3-methyluracil, followed by single-stranded DNA containing 3-methylthymine. Has low demethylase activity towards single-stranded DNA containing 1-methyladenine or 3-methylcytosine. Has no activity towards 1-methylguanine. Has no detectable activity towards double-stranded DNA. Requires molecular oxygen, alpha-ketoglutarate and iron. Contributes to the regulation of the global metabolic rate, energy expenditure and energy homeostasis. Contributes to the regulation of body size and body fat accumulation.[2] [3] Publication Abstract from PubMedThe fat mass and obesity associated protein FTO is a potential target for anti-obesity medicines. FTO is a 2-oxoglutarate (2OG) dependent N-methyl nucleic acid demethylase that acts on substrates including 3-methylthymidine, 3-methyluracil and 6-methyladenine. To identify FTO inhibitors we screened a set of 2OG analogues and related compounds using differential scanning fluorimetry and liquid chromatography based assays. The results revealed sets of both cyclic and acyclic 2OG analogues that are FTO inhibitors. Identified inhibitors include small molecules that have been used in clinical studies for the inhibition of other 2OG oxygenases. Crystallographic analyses reveal inhibition by 2OG co-substrate or primary substrate competitors as well as compounds that bind across both co-substrate and primary substrate binding sites. The results will aid the development of more potent and selective FTO inhibitors. Structural Basis for Inhibition of the Fat Mass and Obesity Associated Protein (FTO).,Aik W, Demetriades M, Hamdan MK, Bagg EA, Yeoh KK, Lejeune C, Zhang Z, McDonough MA, Schofield CJ J Med Chem. 2013 Apr 2. PMID:23547775[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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