6ksf: Difference between revisions
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==Crystal Structure of ALKBH1 bound to 21-mer DNA bulge== | |||
<StructureSection load='6ksf' size='340' side='right'caption='[[6ksf]], [[Resolution|resolution]] 2.40Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6ksf]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KSF OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6KSF FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=SIN:SUCCINIC+ACID'>SIN</scene>, <scene name='pdbligand=XL3:PROPANE-1-THIOL'>XL3</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6ksf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ksf OCA], [http://pdbe.org/6ksf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ksf RCSB], [http://www.ebi.ac.uk/pdbsum/6ksf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ksf ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
N(6)-methyladenine (N(6)-mA) of DNA is an emerging epigenetic mark in mammalian genome. Levels of N(6)-mA undergo drastic fluctuation during early embryogenesis, indicative of active regulation. Here we show that the 2-oxoglutarate-dependent oxygenase ALKBH1 functions as a nuclear eraser of N(6)-mA in unpairing regions (e.g., SIDD, Stress-Induced DNA Double Helix Destabilization regions) of mammalian genomes. Enzymatic profiling studies revealed that ALKBH1 prefers bubbled or bulged DNAs as substrate, instead of single-stranded (ss-) or double-stranded (ds-) DNAs. Structural studies of ALKBH1 revealed an unexpected "stretch-out" conformation of its "Flip1" motif, a conserved element that usually bends over catalytic center to facilitate substrate base flipping in other DNA demethylases. Thus, lack of a bending "Flip1" explains the observed preference of ALKBH1 for unpairing substrates, in which the flipped N(6)-mA is primed for catalysis. Co-crystal structural studies of ALKBH1 bound to a 21-mer bulged DNA explained the need of both flanking duplexes and a flipped base for recognition and catalysis. Key elements (e.g., an ALKBH1-specific alpha1 helix) as well as residues contributing to structural integrity and catalytic activity were validated by structure-based mutagenesis studies. Furthermore, ssDNA-seq and DIP-seq analyses revealed significant co-occurrence of base unpairing regions with N(6)-mA in mouse genome. Collectively, our biochemical, structural and genomic studies suggest that ALKBH1 is an important DNA demethylase that regulates genome N(6)-mA turnover of unpairing regions associated with dynamic chromosome regulation. | |||
Mammalian ALKBH1 serves as an N(6)-mA demethylase of unpairing DNA.,Zhang M, Yang S, Nelakanti R, Zhao W, Liu G, Li Z, Liu X, Wu T, Xiao A, Li H Cell Res. 2020 Mar;30(3):197-210. doi: 10.1038/s41422-019-0237-5. Epub 2020 Feb, 12. PMID:32051560<ref>PMID:32051560</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6ksf" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Li, H]] | |||
[[Category: Zhang, M]] | |||
[[Category: Complex]] | |||
[[Category: Demethylase]] | |||
[[Category: Dna methylation]] | |||
[[Category: Gene regulation]] | |||
Revision as of 09:48, 8 April 2020
Crystal Structure of ALKBH1 bound to 21-mer DNA bulgeCrystal Structure of ALKBH1 bound to 21-mer DNA bulge
Structural highlights
Publication Abstract from PubMedN(6)-methyladenine (N(6)-mA) of DNA is an emerging epigenetic mark in mammalian genome. Levels of N(6)-mA undergo drastic fluctuation during early embryogenesis, indicative of active regulation. Here we show that the 2-oxoglutarate-dependent oxygenase ALKBH1 functions as a nuclear eraser of N(6)-mA in unpairing regions (e.g., SIDD, Stress-Induced DNA Double Helix Destabilization regions) of mammalian genomes. Enzymatic profiling studies revealed that ALKBH1 prefers bubbled or bulged DNAs as substrate, instead of single-stranded (ss-) or double-stranded (ds-) DNAs. Structural studies of ALKBH1 revealed an unexpected "stretch-out" conformation of its "Flip1" motif, a conserved element that usually bends over catalytic center to facilitate substrate base flipping in other DNA demethylases. Thus, lack of a bending "Flip1" explains the observed preference of ALKBH1 for unpairing substrates, in which the flipped N(6)-mA is primed for catalysis. Co-crystal structural studies of ALKBH1 bound to a 21-mer bulged DNA explained the need of both flanking duplexes and a flipped base for recognition and catalysis. Key elements (e.g., an ALKBH1-specific alpha1 helix) as well as residues contributing to structural integrity and catalytic activity were validated by structure-based mutagenesis studies. Furthermore, ssDNA-seq and DIP-seq analyses revealed significant co-occurrence of base unpairing regions with N(6)-mA in mouse genome. Collectively, our biochemical, structural and genomic studies suggest that ALKBH1 is an important DNA demethylase that regulates genome N(6)-mA turnover of unpairing regions associated with dynamic chromosome regulation. Mammalian ALKBH1 serves as an N(6)-mA demethylase of unpairing DNA.,Zhang M, Yang S, Nelakanti R, Zhao W, Liu G, Li Z, Liu X, Wu T, Xiao A, Li H Cell Res. 2020 Mar;30(3):197-210. doi: 10.1038/s41422-019-0237-5. Epub 2020 Feb, 12. PMID:32051560[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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