2iuw

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of human ABH3 in complex with iron ion and 2- oxoglutarate

Structural highlights

2iuw 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 1.5Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ALKB3_HUMAN Dioxygenase that mediates demethylation of DNA and RNA containing 1-methyladenosine (m1A) (PubMed:12486230, PubMed:12594517, PubMed:16174769, PubMed:26863196, PubMed:26863410). Repairs alkylated DNA containing 1-methyladenosine (m1A) and 3-methylcytosine (m3C) by oxidative demethylation (PubMed:12486230, PubMed:12594517, PubMed:16174769, PubMed:25944111). Has a strong preference for single-stranded DNA (PubMed:12486230, PubMed:12594517, PubMed:16174769, PubMed:20714506). Able to process alkylated m3C within double-stranded regions via its interaction with ASCC3, which promotes DNA unwinding to generate single-stranded substrate needed for ALKBH3 (PubMed:22055184). Can repair exocyclic 3,N4-ethenocytosine adducs in single-stranded DNA (PubMed:25797601). Also acts on RNA (PubMed:12594517, PubMed:16174769, PubMed:16858410, PubMed:26863196, PubMed:26863410). Demethylates N(1)-methyladenosine (m1A) RNA, an epigenetic internal modification of messenger RNAs (mRNAs) highly enriched within 5'-untranslated regions (UTRs) and in the vicinity of start codons (PubMed:26863196, PubMed:26863410). Requires molecular oxygen, alpha-ketoglutarate and iron (PubMed:16858410, PubMed:22055184).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Methylating agents are ubiquitous in the environment, and central in cancer therapy. The 1-methyladenine and 3-methylcytosine lesions in DNA/RNA contribute to the cytotoxicity of such agents. These lesions are directly reversed by ABH3 (hABH3) in humans and AlkB in Escherichia coli. Here, we report the structure of the hABH3 catalytic core in complex with iron and 2-oxoglutarate (2OG) at 1.5 A resolution and analyse key site-directed mutants. The hABH3 structure reveals the beta-strand jelly-roll fold that coordinates a catalytically active iron centre by a conserved His1-X-Asp/Glu-X(n)-His2 motif. This experimentally establishes hABH3 as a structural member of the Fe(II)/2OG-dependent dioxygenase superfamily, which couples substrate oxidation to conversion of 2OG into succinate and CO2. A positively charged DNA/RNA binding groove indicates a distinct nucleic acid binding conformation different from that predicted in the AlkB structure with three nucleotides. These results uncover previously unassigned key catalytic residues, identify a flexible hairpin involved in nucleotide flipping and ss/ds-DNA discrimination, and reveal self-hydroxylation of an active site leucine that may protect against uncoupled generation of dangerous oxygen radicals.

Human ABH3 structure and key residues for oxidative demethylation to reverse DNA/RNA damage.,Sundheim O, Vagbo CB, Bjoras M, Sousa MM, Talstad V, Aas PA, Drablos F, Krokan HE, Tainer JA, Slupphaug G EMBO J. 2006 Jul 26;25(14):3389-97. Epub 2006 Jul 6. PMID:16858410^[10]

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

References

↑ Duncan T, Trewick SC, Koivisto P, Bates PA, Lindahl T, Sedgwick B. Reversal of DNA alkylation damage by two human dioxygenases. Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16660-5. Epub 2002 Dec 16. PMID:12486230 doi:10.1073/pnas.262589799
↑ Aas PA, Otterlei M, Falnes PO, Vagbo CB, Skorpen F, Akbari M, Sundheim O, Bjoras M, Slupphaug G, Seeberg E, Krokan HE. Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA. Nature. 2003 Feb 20;421(6925):859-63. PMID:12594517 doi:10.1038/nature01363
↑ Lee DH, Jin SG, Cai S, Chen Y, Pfeifer GP, O'Connor TR. Repair of methylation damage in DNA and RNA by mammalian AlkB homologues. J Biol Chem. 2005 Nov 25;280(47):39448-59. Epub 2005 Sep 20. PMID:16174769 doi:M509881200
↑ Sundheim O, Vagbo CB, Bjoras M, Sousa MM, Talstad V, Aas PA, Drablos F, Krokan HE, Tainer JA, Slupphaug G. Human ABH3 structure and key residues for oxidative demethylation to reverse DNA/RNA damage. EMBO J. 2006 Jul 26;25(14):3389-97. Epub 2006 Jul 6. PMID:16858410
↑ Dango S, Mosammaparast N, Sowa ME, Xiong LJ, Wu F, Park K, Rubin M, Gygi S, Harper JW, Shi Y. DNA unwinding by ASCC3 helicase is coupled to ALKBH3-dependent DNA alkylation repair and cancer cell proliferation. Mol Cell. 2011 Nov 4;44(3):373-84. PMID:22055184 doi:10.1016/j.molcel.2011.08.039
↑ Zdżalik D, Domańska A, Prorok P, Kosicki K, van den Born E, Falnes PØ, Rizzo CJ, Guengerich FP, Tudek B. Differential repair of etheno-DNA adducts by bacterial and human AlkB proteins. DNA Repair (Amst). 2015 Jun;30:1-10. PMID:25797601 doi:10.1016/j.dnarep.2015.02.021
↑ Zhao Y, Majid MC, Soll JM, Brickner JR, Dango S, Mosammaparast N. Noncanonical regulation of alkylation damage resistance by the OTUD4 deubiquitinase. EMBO J. 2015 Jun 12;34(12):1687-703. doi: 10.15252/embj.201490497. Epub 2015 May , 5. PMID:25944111 doi:http://dx.doi.org/10.15252/embj.201490497
↑ Dominissini D, Nachtergaele S, Moshitch-Moshkovitz S, Peer E, Kol N, Ben-Haim MS, Dai Q, Di Segni A, Salmon-Divon M, Clark WC, Zheng G, Pan T, Solomon O, Eyal E, Hershkovitz V, Han D, Doré LC, Amariglio N, Rechavi G, He C. The dynamic N(1)-methyladenosine methylome in eukaryotic messenger RNA. Nature. 2016 Feb 25;530(7591):441-6. PMID:26863196 doi:10.1038/nature16998
↑ Li X, Xiong X, Wang K, Wang L, Shu X, Ma S, Yi C. Transcriptome-wide mapping reveals reversible and dynamic N(1)-methyladenosine methylome. Nat Chem Biol. 2016 May;12(5):311-6. PMID:26863410 doi:10.1038/nchembio.2040
↑ Sundheim O, Vagbo CB, Bjoras M, Sousa MM, Talstad V, Aas PA, Drablos F, Krokan HE, Tainer JA, Slupphaug G. Human ABH3 structure and key residues for oxidative demethylation to reverse DNA/RNA damage. EMBO J. 2006 Jul 26;25(14):3389-97. Epub 2006 Jul 6. PMID:16858410

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2iuw"

@@ Line 3: / Line 3: @@
 <StructureSection load='2iuw' size='340' side='right'caption='[[2iuw]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2iuw]] 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=2IUW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2IUW FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2iuw]] 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=2IUW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IUW FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AKG:2-OXOGLUTARIC+ACID'>AKG</scene>, <scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=FE:FE+(III)+ION'>FE</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]] 1.5&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=LED:(4R)-5-OXO-L-LEUCINE'>LED</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AKG:2-OXOGLUTARIC+ACID'>AKG</scene>, <scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=FE:FE+(III)+ION'>FE</scene>, <scene name='pdbligand=LED:(4R)-5-OXO-L-LEUCINE'>LED</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=2iuw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2iuw OCA], [http://pdbe.org/2iuw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2iuw RCSB], [http://www.ebi.ac.uk/pdbsum/2iuw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2iuw 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=2iuw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2iuw OCA], [https://pdbe.org/2iuw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2iuw RCSB], [https://www.ebi.ac.uk/pdbsum/2iuw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2iuw ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/ALKB3_HUMAN ALKB3_HUMAN] Dioxygenase that mediates demethylation of DNA and RNA containing 1-methyladenosine (m1A) (PubMed:12486230, PubMed:12594517, PubMed:16174769, PubMed:26863196, PubMed:26863410). Repairs alkylated DNA containing 1-methyladenosine (m1A) and 3-methylcytosine (m3C) by oxidative demethylation (PubMed:12486230, PubMed:12594517, PubMed:16174769, PubMed:25944111). Has a strong preference for single-stranded DNA (PubMed:12486230, PubMed:12594517, PubMed:16174769, PubMed:20714506). Able to process alkylated m3C within double-stranded regions via its interaction with ASCC3, which promotes DNA unwinding to generate single-stranded substrate needed for ALKBH3 (PubMed:22055184). Can repair exocyclic 3,N4-ethenocytosine adducs in single-stranded DNA (PubMed:25797601). Also acts on RNA (PubMed:12594517, PubMed:16174769, PubMed:16858410, PubMed:26863196, PubMed:26863410). Demethylates N(1)-methyladenosine (m1A) RNA, an epigenetic internal modification of messenger RNAs (mRNAs) highly enriched within 5'-untranslated regions (UTRs) and in the vicinity of start codons (PubMed:26863196, PubMed:26863410). Requires molecular oxygen, alpha-ketoglutarate and iron (PubMed:16858410, PubMed:22055184).<ref>PMID:12486230</ref> <ref>PMID:12594517</ref> <ref>PMID:16174769</ref> <ref>PMID:16858410</ref> <ref>PMID:22055184</ref> <ref>PMID:25797601</ref> <ref>PMID:25944111</ref> <ref>PMID:26863196</ref> <ref>PMID:26863410</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 13: / Line 15: @@
   <jmolCheckbox>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/iu/2iuw_consurf.spt"</scriptWhenChecked>
-    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
@@ Line 31: / Line 33: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Aas, P A]]
+[[Category: Aas PA]]
-[[Category: Bjoras, M]]
+[[Category: Bjoras M]]
-[[Category: Drablos, F]]
+[[Category: Drablos F]]
-[[Category: Krokan, H E]]
+[[Category: Krokan HE]]
-[[Category: Slupphaug, G]]
+[[Category: Slupphaug G]]
-[[Category: Sundheim, O]]
+[[Category: Sundheim O]]
-[[Category: Tainer, J A]]
+[[Category: Tainer JA]]
-[[Category: Talstad, V]]
+[[Category: Talstad V]]
-[[Category: Vagbo, C B]]
+[[Category: Vagbo CB]]
-[[Category: DeSousa, M M.L]]
+[[Category: DeSousa MML]]
-[[Category: Beta jellyroll]]
-[[Category: Demethylase]]
-[[Category: Dna/rna repair]]
-[[Category: Oxidoreductase]]

2iuw

From Proteopedia

Current revision

Crystal structure of human ABH3 in complex with iron ion and 2- oxoglutarate

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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