5zmd

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of FTO in complex with m6dA modified ssDNA

Structural highlights

5zmd is a 8 chain structure with sequence from DNA launch vector pDE-GFP2 and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.3Å
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 demethylates internal N (6)-methyladenosine (m(6)A) and N (6),2'-O-dimethyladenosine (m(6)Am; at the cap +1 position) in mRNA, m(6)A and m(6)Am in snRNA, and N (1)-methyladenosine (m(1)A) in tRNA in vivo, and in vitro evidence supports that it can also demethylate N (6)-methyldeoxyadenosine (6mA), 3-methylthymine (3mT), and 3-methyluracil (m(3)U). However, it remains unclear how FTO variously recognizes and catalyzes these diverse substrates. Here we demonstrate-in vitro and in vivo-that FTO has extensive demethylation enzymatic activity on both internal m(6)A and cap m(6)Am Considering that 6mA, m(6)A, and m(6)Am all share the same nucleobase, we present a crystal structure of human FTO bound to 6mA-modified ssDNA, revealing the molecular basis of the catalytic demethylation of FTO toward multiple RNA substrates. We discovered that (i) N (6)-methyladenine is the most favorable nucleobase substrate of FTO, (ii) FTO displays the same demethylation activity toward internal m(6)A and m(6)Am in the same RNA sequence, suggesting that the substrate specificity of FTO primarily results from the interaction of residues in the catalytic pocket with the nucleobase (rather than the ribose ring), and (iii) the sequence and the tertiary structure of RNA can affect the catalytic activity of FTO. Our findings provide a structural basis for understanding the catalytic mechanism through which FTO demethylates its multiple substrates and pave the way forward for the structure-guided design of selective chemicals for functional studies and potential therapeutic applications.

Structural insights into FTO's catalytic mechanism for the demethylation of multiple RNA substrates.,Zhang X, Wei LH, Wang Y, Xiao Y, Liu J, Zhang W, Yan N, Amu G, Tang X, Zhang L, Jia G Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):2919-2924. doi:, 10.1073/pnas.1820574116. Epub 2019 Feb 4. PMID:30718435^[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
↑ Zhang X, Wei LH, Wang Y, Xiao Y, Liu J, Zhang W, Yan N, Amu G, Tang X, Zhang L, Jia G. Structural insights into FTO's catalytic mechanism for the demethylation of multiple RNA substrates. Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):2919-2924. doi:, 10.1073/pnas.1820574116. Epub 2019 Feb 4. PMID:30718435 doi:http://dx.doi.org/10.1073/pnas.1820574116

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/5zmd"

@@ Line 3: / Line 3: @@
 <StructureSection load='5zmd' size='340' side='right'caption='[[5zmd]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5zmd]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZMD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ZMD FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5zmd]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/DNA_launch_vector_pDE-GFP2 DNA launch vector pDE-GFP2] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZMD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ZMD FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=OGA:N-OXALYLGLYCINE'>OGA</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.3&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=6MA:N6-METHYL-DEOXY-ADENOSINE-5-MONOPHOSPHATE'>6MA</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6MA:N6-METHYL-DEOXY-ADENOSINE-5-MONOPHOSPHATE'>6MA</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=OGA:N-OXALYLGLYCINE'>OGA</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5zmd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zmd OCA], [http://pdbe.org/5zmd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5zmd RCSB], [http://www.ebi.ac.uk/pdbsum/5zmd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5zmd ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5zmd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zmd OCA], [https://pdbe.org/5zmd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5zmd RCSB], [https://www.ebi.ac.uk/pdbsum/5zmd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5zmd ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/FTO_HUMAN FTO_HUMAN]] Defects in FTO are the cause of growth retardation developmental delay coarse facies and early death (GDFD) [MIM:[http://omim.org/entry/612938 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.<ref>PMID:19559399</ref>
+[https://www.uniprot.org/uniprot/FTO_HUMAN FTO_HUMAN] Defects in FTO are the cause of growth retardation developmental delay coarse facies and early death (GDFD) [MIM:[https://omim.org/entry/612938 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.<ref>PMID:19559399</ref>
 == 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>
+[https://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 ==
@@ Line 21: / Line 21: @@
 </div>
 <div class="pdbe-citations 5zmd" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Dioxygenase 3D structures|Dioxygenase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: DNA launch vector pDE-GFP2]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Jia, G F]]
+[[Category: Jia GF]]
-[[Category: Liu, J]]
+[[Category: Liu J]]
-[[Category: Luo, J]]
+[[Category: Luo J]]
-[[Category: Wei, L H]]
+[[Category: Wei LH]]
-[[Category: Xiao, Y]]
+[[Category: Xiao Y]]
-[[Category: Zhang, L]]
+[[Category: Zhang L]]
-[[Category: Zhang, W]]
+[[Category: Zhang W]]
-[[Category: Zhang, X]]
+[[Category: Zhang X]]
-[[Category: M6a]]
-[[Category: Oxidoreductase-dna complex]]
-[[Category: Rna binding protein]]
-[[Category: Rna demetheylase fto]]
-[[Category: Substrate preference]]

5zmd

From Proteopedia

Current revision

Crystal structure of FTO in complex with m6dA modified ssDNA

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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