7v4g
From Proteopedia
(Difference between revisions)
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- | ==== | + | ==Crystal structure of human ALKBH5 in complex with m6A-containing ssRNA== |
- | <StructureSection load='7v4g' size='340' side='right'caption='[[7v4g]]' scene=''> | + | <StructureSection load='7v4g' size='340' side='right'caption='[[7v4g]], [[Resolution|resolution]] 2.10Å' 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= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7v4g]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7V4G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V4G 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=7v4g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v4g OCA], [https://pdbe.org/7v4g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v4g RCSB], [https://www.ebi.ac.uk/pdbsum/7v4g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v4g 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]] 2.1Å</td></tr> |
+ | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6MZ:N6-METHYLADENOSINE-5-MONOPHOSPHATE'>6MZ</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=7v4g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v4g OCA], [https://pdbe.org/7v4g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v4g RCSB], [https://www.ebi.ac.uk/pdbsum/7v4g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v4g ProSAT]</span></td></tr> | ||
</table> | </table> | ||
+ | == Function == | ||
+ | [https://www.uniprot.org/uniprot/ALKB5_HUMAN ALKB5_HUMAN] Dioxygenase that demethylates RNA by oxidative demethylation: specifically demethylates N(6)-methyladenosine (m(6)A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Requires molecular oxygen, alpha-ketoglutarate and iron. Demethylation of m(6)A mRNA affects mRNA processing and export and is required for spermatogenesis.<ref>PMID:21264265</ref> <ref>PMID:23177736</ref> | ||
+ | <div style="background-color:#fffaf0;"> | ||
+ | == Publication Abstract from PubMed == | ||
+ | AlkB homologue 5 (ALKBH5) is a ferrous iron and 2-oxoglutarate dependent oxygenase that demethylates RNA N6-methyladenosine (m6A), a post-transcriptional RNA modification with an emerging set of regulatory roles. Along with the fat mass and obesity-associated protein (FTO), ALKBH5 is one of only two identified human m6A RNA oxidizing enzymes and is a potential target for cancer treatment. Unlike FTO, ALKBH5 efficiently catalyzes fragmentation of its proposed nascent hemiaminal intermediate to give formaldehyde and a demethylated nucleoside. A detailed analysis of the molecular mechanisms used by ALKBH5 for substrate recognition and m6A demethylation is lacking. We report three crystal structures of ALKBH5 in complex with an m6A-ssRNA 8-mer substrate and supporting biochemical analyses. Strikingly, the single-stranded RNA substrate binds to the active site of ALKBH5 in a 5'-3' orientation that is opposite to single-stranded or double-stranded DNA substrates observed for other AlkB subfamily members, including single-stranded DNA bound to FTO. The combined structural and biochemical results provide insight into the preference of ALKBH5 for substrates containing a (A/G)m6AC consensus sequence motif. The results support a mechanism involving formation of an m6A hemiaminal intermediate, followed by efficient ALKBH5 catalyzed demethylation, enabled by a proton shuttle network involving Lys132 and Tyr139. | ||
+ | |||
+ | Mechanisms of substrate recognition and N6-methyladenosine demethylation revealed by crystal structures of ALKBH5-RNA complexes.,Kaur S, Tam NY, McDonough MA, Schofield CJ, Aik WS Nucleic Acids Res. 2022 Apr 22;50(7):4148-4160. doi: 10.1093/nar/gkac195. PMID:35333330<ref>PMID:35333330</ref> | ||
+ | |||
+ | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
+ | </div> | ||
+ | <div class="pdbe-citations 7v4g" style="background-color:#fffaf0;"></div> | ||
+ | |||
+ | ==See Also== | ||
+ | *[[Dioxygenase 3D structures|Dioxygenase 3D structures]] | ||
+ | == References == | ||
+ | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
+ | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
- | [[Category: | + | [[Category: Synthetic construct]] |
+ | [[Category: Aik WS]] | ||
+ | [[Category: Kaur S]] | ||
+ | [[Category: McDonough MA]] | ||
+ | [[Category: Schofield CJ]] |
Current revision
Crystal structure of human ALKBH5 in complex with m6A-containing ssRNA
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