4qkn
From Proteopedia
(Difference between revisions)
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==Crystal structure of FTO bound to a selective inhibitor== | ==Crystal structure of FTO bound to a selective inhibitor== | ||
| - | <StructureSection load='4qkn' size='340' side='right'caption='[[4qkn]]' scene=''> | + | <StructureSection load='4qkn' size='340' side='right'caption='[[4qkn]], [[Resolution|resolution]] 2.20Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QKN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QKN FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4qkn]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QKN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QKN FirstGlance]. <br> |
| - | </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=4qkn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qkn OCA], [https://pdbe.org/4qkn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qkn RCSB], [https://www.ebi.ac.uk/pdbsum/4qkn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qkn ProSAT]</span></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]] 2.2Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JMS:2-[(2,6-DICHLORO-3-METHYL-PHENYL)AMINO]BENZOIC+ACID'>JMS</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'>[https://proteopedia.org/fgij/fg.htm?mol=4qkn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qkn OCA], [https://pdbe.org/4qkn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qkn RCSB], [https://www.ebi.ac.uk/pdbsum/4qkn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qkn ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [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 == | ||
| + | [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 == | ||
| + | Two human demethylases, the fat mass and obesity-associated (FTO) enzyme and ALKBH5, oxidatively demethylate abundant N6-methyladenosine (m6A) residues in mRNA. Achieving a method for selective inhibition of FTO over ALKBH5 remains a challenge, however. Here, we have identified meclofenamic acid (MA) as a highly selective inhibitor of FTO. MA is a non-steroidal, anti-inflammatory drug that mechanistic studies indicate competes with FTO binding for the m6A-containing nucleic acid. The structure of FTO/MA has revealed much about the inhibitory function of FTO. Our newfound understanding, revealed herein, of the part of the nucleotide recognition lid (NRL) in FTO, for example, has helped elucidate the principles behind the selectivity of FTO over ALKBH5. Treatment of HeLa cells with the ethyl ester form of MA (MA2) has led to elevated levels of m6A modification in mRNA. Our collective results highlight the development of functional probes of the FTO enzyme that will (i) enable future biological studies and (ii) pave the way for the rational design of potent and specific inhibitors of FTO for use in medicine. | ||
| + | |||
| + | Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5.,Huang Y, Yan J, Li Q, Li J, Gong S, Zhou H, Gan J, Jiang H, Jia GF, Luo C, Yang CG Nucleic Acids Res. 2014 Dec 1. pii: gku1276. PMID:25452335<ref>PMID:25452335</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 4qkn" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
*[[Dioxygenase 3D structures|Dioxygenase 3D structures]] | *[[Dioxygenase 3D structures|Dioxygenase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Gan J]] | [[Category: Gan J]] | ||
[[Category: Huang Y]] | [[Category: Huang Y]] | ||
[[Category: Yang C-G]] | [[Category: Yang C-G]] | ||
Current revision
Crystal structure of FTO bound to a selective inhibitor
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