4cxy

From Proteopedia

(Difference between revisions)

Revision as of 06:07, 18 April 2018

Crystal structure of human FTO in complex with acylhydrazine inhibitor 21

Structural highlights

4cxy is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	4cxw, 4cxx, 4cxz, 4cy0
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

The AlkB family of nucleic acid demethylases are of intense biological and medical interest because of their roles in nucleic acid repair and epigenetic modification. However their functional and molecular mechanisms are unclear, hence, there is strong interest in developing selective inhibitors for them. Here we report the identification of key residues within the nucleotide-binding sites of the AlkB subfamilies that likely determine their substrate specificity. We further provide proof of principle that a strategy exploiting these inherent structural differences can enable selective and potent inhibition of the AlkB subfamilies. This is demonstrated by the first report of a subfamily-selective and cell-active FTO inhibitor 12. The distinct selectivity of 12 for FTO against other AlkB subfamilies and 2OG oxygenases shall be of considerable interest with regards to its potential use as a functional probe. The strategy outlined here is likely applicable to other AlkB subfamilies, and, more widely, to other 2OG oxygenases.

A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N(6)-methyladenosine demethylase FTO.,Toh JDW, Sun L, Lau LZM, Tan J, Low JJA, Tang CWQ, Cheong EJY, Tan MJH, Chen Y, Hong W, Gao YG, Woon ECY Chem Sci. 2015 Jan 1;6(1):112-122. doi: 10.1039/c4sc02554g. Epub 2014 Sep 22. PMID:28553460^[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
↑ Toh JDW, Sun L, Lau LZM, Tan J, Low JJA, Tang CWQ, Cheong EJY, Tan MJH, Chen Y, Hong W, Gao YG, Woon ECY. A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N(6)-methyladenosine demethylase FTO. Chem Sci. 2015 Jan 1;6(1):112-122. doi: 10.1039/c4sc02554g. Epub 2014 Sep 22. PMID:28553460 doi:http://dx.doi.org/10.1039/c4sc02554g

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4cxy"

@@ Line 3: / Line 3: @@
 <StructureSection load='4cxy' size='340' side='right' caption='[[4cxy]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4cxy]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CXY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CXY FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4cxy]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CXY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CXY FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DGR:(E)-4-(2-NICOTINOYLHYDRAZINYL)-4-OXOBUT-2-ENOIC+ACID'>DGR</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4cxw|4cxw]], [[4cxx|4cxx]], [[4cxz|4cxz]], [[4cy0|4cy0]]</td></tr>
@@ Line 12: / Line 12: @@
 == Function ==
 [[http://www.uniprot.org/uniprot/FTO_HUMAN 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.<ref>PMID:18775698</ref> <ref>PMID:20376003</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The AlkB family of nucleic acid demethylases are of intense biological and medical interest because of their roles in nucleic acid repair and epigenetic modification. However their functional and molecular mechanisms are unclear, hence, there is strong interest in developing selective inhibitors for them. Here we report the identification of key residues within the nucleotide-binding sites of the AlkB subfamilies that likely determine their substrate specificity. We further provide proof of principle that a strategy exploiting these inherent structural differences can enable selective and potent inhibition of the AlkB subfamilies. This is demonstrated by the first report of a subfamily-selective and cell-active FTO inhibitor 12. The distinct selectivity of 12 for FTO against other AlkB subfamilies and 2OG oxygenases shall be of considerable interest with regards to its potential use as a functional probe. The strategy outlined here is likely applicable to other AlkB subfamilies, and, more widely, to other 2OG oxygenases.
+A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N(6)-methyladenosine demethylase FTO.,Toh JDW, Sun L, Lau LZM, Tan J, Low JJA, Tang CWQ, Cheong EJY, Tan MJH, Chen Y, Hong W, Gao YG, Woon ECY Chem Sci. 2015 Jan 1;6(1):112-122. doi: 10.1039/c4sc02554g. Epub 2014 Sep 22. PMID:28553460<ref>PMID:28553460</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 4cxy" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 19: / Line 28: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Chen, Y]]
 [[Category: Gao, Y G]]

4cxy

From Proteopedia

Revision as of 06:07, 18 April 2018

Crystal structure of human FTO in complex with acylhydrazine inhibitor 21

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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