7nro

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==Crystal structure of AlkB in complex with manganese and N-(4-((6-((carboxymethyl)carbamoyl)-5-hydroxypyridin-2-yl)amino)phenyl)-N-oxohydroxylammonium==
==Crystal structure of AlkB in complex with manganese and N-(4-((6-((carboxymethyl)carbamoyl)-5-hydroxypyridin-2-yl)amino)phenyl)-N-oxohydroxylammonium==
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<StructureSection load='7nro' size='340' side='right'caption='[[7nro]]' scene=''>
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<StructureSection load='7nro' size='340' side='right'caption='[[7nro]], [[Resolution|resolution]] 1.25&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NRO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NRO FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7nro]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NRO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NRO FirstGlance]. <br>
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</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=7nro FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nro OCA], [https://pdbe.org/7nro PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nro RCSB], [https://www.ebi.ac.uk/pdbsum/7nro PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nro ProSAT]</span></td></tr>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=UPW:2-[[6-[(4-nitrophenyl)amino]-3-oxidanyl-pyridin-2-yl]carbonylamino]ethanoic+acid'>UPW</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3t3y|3t3y]]</div></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/DNA_oxidative_demethylase DNA oxidative demethylase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.11.33 1.14.11.33] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7nro FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nro OCA], [https://pdbe.org/7nro PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nro RCSB], [https://www.ebi.ac.uk/pdbsum/7nro PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nro ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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[[https://www.uniprot.org/uniprot/ALKB_ECOLI ALKB_ECOLI]] Dioxygenase that repairs alkylated DNA and RNA containing 3-methylcytosine or 1-methyladenine by oxidative demethylation. Has highest activity towards 3-methylcytosine. Has lower activity towards alkylated DNA containing ethenoadenine, and no detectable activity towards 1-methylguanine or 3-methylthymine. Accepts double-stranded and single-stranded substrates. Requires molecular oxygen, alpha-ketoglutarate and iron. Provides extensive resistance to alkylating agents such as MMS and DMS (SN2 agents), but not to MMNG and MNU (SN1 agents).<ref>PMID:12226668</ref> <ref>PMID:12594517</ref> <ref>PMID:16482161</ref> <ref>PMID:19706517</ref> <ref>PMID:21068844</ref> <ref>PMID:20084272</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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FTO catalyzes the Fe(II) and 2-oxoglutarate (2OG)-dependent modification of nucleic acids, including the demethylation of N(6)-methyladenosine (m(6)A) in mRNA. FTO is a proposed target for anti-cancer therapy. Using information from crystal structures of FTO in complex with 2OG and substrate mimics, we designed and synthesized two series of FTO inhibitors, which were characterized by turnover and binding assays, and by X-ray crystallography with FTO and the related bacterial enzyme AlkB. A potent inhibitor employing binding interactions spanning the FTO 2OG and substrate binding sites was identified. Selectivity over other clinically targeted 2OG oxygenases was demonstrated, including with respect to the hypoxia-inducible factor prolyl and asparaginyl hydroxylases (PHD2 and FIH) and selected JmjC histone demethylases (KDMs). The results illustrate how structure-based design can enable the identification of potent and selective 2OG oxygenase inhibitors and will be useful for the development of FTO inhibitors for use in vivo.
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Structure-Based Design of Selective Fat Mass and Obesity Associated Protein (FTO) Inhibitors.,Shishodia S, Demetriades M, Zhang D, Tam NY, Maheswaran P, Clunie-O'Connor C, Tumber A, Leung IKH, Ng YM, Leissing TM, El-Sagheer AH, Salah E, Brown T, Aik WS, McDonough MA, Schofield CJ J Med Chem. 2021 Nov 11. doi: 10.1021/acs.jmedchem.1c01204. PMID:34762429<ref>PMID:34762429</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7nro" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: DNA oxidative demethylase]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Aik WS]]
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[[Category: Aik, W S]]
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[[Category: Leissing T]]
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[[Category: Leissing, T]]
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[[Category: Maheswaran P]]
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[[Category: Maheswaran, P]]
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[[Category: McDonough MA]]
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[[Category: McDonough, M A]]
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[[Category: Schofield CJ]]
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[[Category: Schofield, C J]]
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[[Category: Shishodia, S]]
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[[Category: Alpha ketoglutarate and iron dependent oxygenase]]
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[[Category: Dna demethylase]]
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[[Category: Inhibitor complex]]
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[[Category: Oxidoreductase]]

Revision as of 12:48, 24 November 2021

Crystal structure of AlkB in complex with manganese and N-(4-((6-((carboxymethyl)carbamoyl)-5-hydroxypyridin-2-yl)amino)phenyl)-N-oxohydroxylammonium

PDB ID 7nro

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