9ky4: Difference between revisions
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==Cryo-EM structure of the mono-DdCBE bound TS substrate complex.== | |||
<StructureSection load='9ky4' size='340' side='right'caption='[[9ky4]], [[Resolution|resolution]] 3.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[9ky4]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Burkholderia_cenocepacia_H111 Burkholderia cenocepacia H111], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Xanthomonas Xanthomonas]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9KY4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9KY4 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</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=9ky4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9ky4 OCA], [https://pdbe.org/9ky4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9ky4 RCSB], [https://www.ebi.ac.uk/pdbsum/9ky4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9ky4 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/DDDA_BURC1 DDDA_BURC1] Toxic component of a toxin-immunity protein module, which functions as a cellular contact-dependent growth inhibition (CDI) system. CDI modules allow bacteria to communicate with and inhibit the growth of closely related neighboring bacteria in a contact-dependent fashion. Bacteria that have this module inhibit or kill bacteria without it, giving them a growth advantage. Probably specifically inhibited by cognate immunity protein DddI (Probable). The C-terminal 163 residue fragment has double-stranded DNA cytidine deaminase activity; it does not deaminate ssDNA, ssRNA or dsRNA. Leads to C:G to T:A conversions in deaminated DNA. Preferentially deaminates 5'-TC-3' substrates (PubMed:32641830).<ref>PMID:32641830</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
DddA-derived cytosine base editor (DdCBE) couples transcription activator-like effector (TALE) arrays and the double-stranded DNA (dsDNA)-specific cytidine deaminase DddA to target mitochondrial DNA (mtDNA) for editing. However, structures of DdCBE in action are unavailable, impeding its mechanistic-based optimization for high-precision-demanding therapeutic applications. Here, we determined the cryo-electron microscopy (cryo-EM) structures of DdCBE targeting two native mitochondrial gene loci and combined editing data from systematically designed spacers to develop WinPred, a model that can predict DdCBE's editing outcome and guide its design to achieve high-precision editing. Furthermore, structure-guided engineering of DddA narrowed the editing window of DdCBE to 2-3 nt while minimizing its off-target (OT) editing to near-background levels, thereby generating accurate DdCBE (aDdCBE). Using aDdCBE, we precisely introduced a Leber hereditary optic neuropathy (LHON)-disease-related mutation into mtDNA and faithfully recapitulated the pathogenic conditions without interference from unintended bystander or OT mutations. Our work provides a mechanistic understanding of DdCBE and establishes WinPred and aDdCBE as useful tools for faithfully modeling or correcting disease-related mtDNA mutations. | |||
Structural insights into DdCBE in action enable high-precision mitochondrial DNA editing.,Xiang J, Xu W, Wu J, Luo Y, Liu C, Hou Y, Chen J, Yang B Mol Cell. 2025 Sep 18;85(18):3357-3372.e9. doi: 10.1016/j.molcel.2025.08.016. , Epub 2025 Sep 10. PMID:40934924<ref>PMID:40934924</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 9ky4" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Burkholderia cenocepacia H111]] | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Xanthomonas]] | |||
[[Category: Bei Y]] | |||
[[Category: Jia C]] | |||
[[Category: Jiangchao X]] | |||
