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| Title | Computational design of a high-precision mitochondrial DNA cytosine base editor. |
|---|---|
| Journal, issue, pages | Nat Struct Mol Biol, Vol. 32, Issue 12, Page 2575-2586, Year 2025 |
| Publish date | Nov 17, 2025 |
 Authors | Li Mi / Yu-Xuan Li / Xinchen Lv / Zi-Li Wan / Xu Liu / Kairan Zhang / Huican Li / Yue Yao / Leping Zhang / Zhe Xu / Xingyu Zhuang / Kunqian Ji / Min Jiang / Yangming Wang / Peilong Lu /  |
| PubMed Abstract | Bystander editing remains a major limitation of current base editors, hindering their precision and therapeutic potential. Here, we present a de novo protein design strategy that creates a ...Bystander editing remains a major limitation of current base editors, hindering their precision and therapeutic potential. Here, we present a de novo protein design strategy that creates a structurally rigid interface between a DNA-binding TALE domain and a cytosine deaminase, forming a unified editing module termed TALE-oriented deaminase (TOD). Cryo-EM analysis of TOD-DNA complexes confirms that this precise spatial architecture tightly restricts the deaminase activity window, thereby minimizing unwanted deamination. To further enhance editing specificity, we develop a split version, termed DdCBE-TOD, which virtually eliminates off-target editing. As a proof of concept, we apply DdCBE-TOD to generate a mitochondrial disease mouse model and to correct a pathogenic mutation associated with MERRF syndrome in patient-derived cells, achieving single-nucleotide precision. This work introduces a generalizable and computationally guided approach for ultra-precise base editing, offering a promising platform for both mechanistic studies and therapeutic correction of single-nucleotide mutations. |
 External links | Nat Struct Mol Biol / PubMed:41249818 |
| Methods | EM (single particle) |
| Resolution | 2.64 - 3.18 Å |
| Structure data | EMDB-62995, PDB-9lcx: EMDB-62996, PDB-9lcy: EMDB-62997, PDB-9lcz: EMDB-62998, PDB-9ld0: EMDB-62999, PDB-9ld1: |
| Chemicals |  ChemComp-ZN: |
| Source |
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 Keywords | DE NOVO PROTEIN / De novo design / DNA-binding TALE domain / deaminase (Ddd_Ss) / orienting domain / deaminase(Ddd_Ss) |
burkholderia cenocepacia (bacteria)