View source for 8jnr


==Crystal structure of human ALKBH3 bound to 3mC containing ssDNA through distal crosslink==
<StructureSection load='8jnr' size='340' side='right'caption='[[8jnr]], [[Resolution|resolution]] 3.66&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8jnr]] is a 14 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=8JNR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8JNR FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.66&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ME6:[(2R,3S,5R)-5-(4-AZANYL-3-METHYL-2-OXO-PYRIMIDIN-3-IUM-1-YL)-3-HYDROXY-OXOLAN-2-YL]METHYL+DIHYDROGEN+PHOSPHATE'>ME6</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=8jnr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8jnr OCA], [https://pdbe.org/8jnr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8jnr RCSB], [https://www.ebi.ac.uk/pdbsum/8jnr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8jnr 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> 
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== Publication Abstract from PubMed ==
N(1) -methyladenosine (m(1) A) is a prevalent post-transcriptional RNA modification, and the distribution and dynamics of the modification play key epitranscriptomic roles in cell development. At present, the human AlkB Fe(II)/alpha-ketoglutarate-dependent dioxygenase family member ALKBH3 is the only known mRNA m(1) A demethylase, but its catalytic mechanism remains unclear. Here, we present the structures of ALKBH3-oligo crosslinked complexes obtained with the assistance of a synthetic antibody crystallization chaperone. Structural and biochemical results showed that ALKBH3 utilized two beta-hairpins (beta4-loop-beta5 and beta'-loop-beta'') and the alpha2 helix to facilitate single-stranded substrate binding. Moreover, a bubble-like region around Asp194 and a key residue inside the active pocket (Thr133) enabled specific recognition and demethylation of m(1) A- and 3-methylcytidine (m(3) C)-modified substrates. Mutation of Thr133 to the corresponding residue in the AlkB Fe(II)/alpha-ketoglutarate-dependent dioxygenase family members FTO or ALKBH5 converted ALKBH3 substrate selectivity from m(1) A to N(6) -methyladenosine (m(6) A), as did Asp194 deletion. Our findings provide a molecular basis for understanding the mechanisms of substrate recognition and m(1) A demethylation by ALKBH3. This study is expected to aid structure-guided design of chemical probes for further functional studies and therapeutic applications.

The Molecular Basis of Human ALKBH3 Mediated RNA N(1) -methyladenosine (m(1) A) Demethylation.,Zhang L, Duan HC, Paduch M, Hu J, Zhang C, Mu Y, Lin H, He C, Kossiakoff AA, Jia G, Zhang L Angew Chem Int Ed Engl. 2024 Feb 12;63(7):e202313900. doi: , 10.1002/anie.202313900. Epub 2024 Jan 11. PMID:38158383<ref>PMID:38158383</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8jnr" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Zhang L]]