6akw

Crystal structure of RNA dioxygenase bound with an inhibitorCrystal structure of RNA dioxygenase bound with an inhibitor

Structural highlights

6akw is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.2Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

FTO, an mRNA N(6)-methyladenosine (m(6)A) demethylase, was reported to promote leukemogenesis. Using structure-based rational design, we have developed two promising FTO inhibitors, namely FB23 and FB23-2, which directly bind to FTO and selectively inhibit FTO's m(6)A demethylase activity. Mimicking FTO depletion, FB23-2 dramatically suppresses proliferation and promotes the differentiation/apoptosis of human acute myeloid leukemia (AML) cell line cells and primary blast AML cells in vitro. Moreover, FB23-2 significantly inhibits the progression of human AML cell lines and primary cells in xeno-transplanted mice. Collectively, our data suggest that FTO is a druggable target and that targeting FTO by small-molecule inhibitors holds potential to treat AML.

Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia.,Huang Y, Su R, Sheng Y, Dong L, Dong Z, Xu H, Ni T, Zhang ZS, Zhang T, Li C, Han L, Zhu Z, Lian F, Wei J, Deng Q, Wang Y, Wunderlich M, Gao Z, Pan G, Zhong D, Zhou H, Zhang N, Gan J, Jiang H, Mulloy JC, Qian Z, Chen J, Yang CG Cancer Cell. 2019 Apr 15;35(4):677-691.e10. doi: 10.1016/j.ccell.2019.03.006. PMID:30991027^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Boissel S, Reish O, Proulx K, Kawagoe-Takaki H, Sedgwick B, Yeo GS, Meyre D, Golzio C, Molinari F, Kadhom N, Etchevers HC, Saudek V, Farooqi IS, Froguel P, Lindahl T, O'Rahilly S, Munnich A, Colleaux L. Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am J Hum Genet. 2009 Jul;85(1):106-11. doi: 10.1016/j.ajhg.2009.06.002. Epub 2009, Jun 25. PMID:19559399 doi:10.1016/j.ajhg.2009.06.002
↑ Jia G, Yang CG, Yang S, Jian X, Yi C, Zhou Z, He C. Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human FTO. FEBS Lett. 2008 Oct 15;582(23-24):3313-9. doi: 10.1016/j.febslet.2008.08.019., Epub 2008 Sep 5. PMID:18775698 doi:10.1016/j.febslet.2008.08.019
↑ Han Z, Niu T, Chang J, Lei X, Zhao M, Wang Q, Cheng W, Wang J, Feng Y, Chai J. Crystal structure of the FTO protein reveals basis for its substrate specificity. Nature. 2010 Apr 22;464(7292):1205-9. Epub 2010 Apr 7. PMID:20376003 doi:10.1038/nature08921
↑ Huang Y, Su R, Sheng Y, Dong L, Dong Z, Xu H, Ni T, Zhang ZS, Zhang T, Li C, Han L, Zhu Z, Lian F, Wei J, Deng Q, Wang Y, Wunderlich M, Gao Z, Pan G, Zhong D, Zhou H, Zhang N, Gan J, Jiang H, Mulloy JC, Qian Z, Chen J, Yang CG. Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia. Cancer Cell. 2019 Apr 15;35(4):677-691.e10. doi: 10.1016/j.ccell.2019.03.006. PMID:30991027 doi:http://dx.doi.org/10.1016/j.ccell.2019.03.006

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Boissel S, Reish O, Proulx K, Kawagoe-Takaki H, Sedgwick B, Yeo GS, Meyre D, Golzio C, Molinari F, Kadhom N, Etchevers HC, Saudek V, Farooqi IS, Froguel P, Lindahl T, O'Rahilly S, Munnich A, Colleaux L. Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am J Hum Genet. 2009 Jul;85(1):106-11. doi: 10.1016/j.ajhg.2009.06.002. Epub 2009, Jun 25. PMID:19559399 doi:10.1016/j.ajhg.2009.06.002

[2] Jia G, Yang CG, Yang S, Jian X, Yi C, Zhou Z, He C. Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human FTO. FEBS Lett. 2008 Oct 15;582(23-24):3313-9. doi: 10.1016/j.febslet.2008.08.019., Epub 2008 Sep 5. PMID:18775698 doi:10.1016/j.febslet.2008.08.019

[3] Han Z, Niu T, Chang J, Lei X, Zhao M, Wang Q, Cheng W, Wang J, Feng Y, Chai J. Crystal structure of the FTO protein reveals basis for its substrate specificity. Nature. 2010 Apr 22;464(7292):1205-9. Epub 2010 Apr 7. PMID:20376003 doi:10.1038/nature08921

[4] Huang Y, Su R, Sheng Y, Dong L, Dong Z, Xu H, Ni T, Zhang ZS, Zhang T, Li C, Han L, Zhu Z, Lian F, Wei J, Deng Q, Wang Y, Wunderlich M, Gao Z, Pan G, Zhong D, Zhou H, Zhang N, Gan J, Jiang H, Mulloy JC, Qian Z, Chen J, Yang CG. Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia. Cancer Cell. 2019 Apr 15;35(4):677-691.e10. doi: 10.1016/j.ccell.2019.03.006. PMID:30991027 doi:http://dx.doi.org/10.1016/j.ccell.2019.03.006

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