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8FIK

APOBEC3A E72A inactive mutant in complex with ATTC-hairpin DNA substrate

8FIK の概要
エントリーDOI10.2210/pdb8fik/pdb
分子名称DNA dC->dU-editing enzyme APOBEC-3A, DNA (5'-D(P*CP*CP*CP*AP*TP*CP*AP*TP*TP*CP*GP*AP*TP*GP*GP*G)-3'), ZINC ION, ... (7 entities in total)
機能のキーワードapobec, apobec3a, a3a, cancer, dna, mutation, cytidine deaminase, hairpin dna, dna binding protein, dna binding protein-dna complex, dna binding protein/dna
由来する生物種Homo sapiens (human)
詳細
タンパク質・核酸の鎖数4
化学式量合計56860.96
構造登録者
Harjes, S.,Jameson, G.B.,Harjes, E.,Filichev, V.V.,Kurup, H.M. (登録日: 2022-12-16, 公開日: 2023-09-06, 最終更新日: 2024-09-18)
主引用文献Harjes, S.,Kurup, H.M.,Rieffer, A.E.,Bayarjargal, M.,Filitcheva, J.,Su, Y.,Hale, T.K.,Filichev, V.V.,Harjes, E.,Harris, R.S.,Jameson, G.B.
Structure-guided inhibition of the cancer DNA-mutating enzyme APOBEC3A.
Nat Commun, 14:6382-6382, 2023
Cited by
PubMed Abstract: The normally antiviral enzyme APOBEC3A is an endogenous mutagen in human cancer. Its single-stranded DNA C-to-U editing activity results in multiple mutagenic outcomes including signature single-base substitution mutations (isolated and clustered), DNA breakage, and larger-scale chromosomal aberrations. APOBEC3A inhibitors may therefore comprise a unique class of anti-cancer agents that work by blocking mutagenesis, slowing tumor evolvability, and preventing detrimental outcomes such as drug resistance and metastasis. Here we reveal the structural basis of competitive inhibition of wildtype APOBEC3A by hairpin DNA bearing 2'-deoxy-5-fluorozebularine in place of the cytidine in the TC substrate motif that is part of a 3-nucleotide loop. In addition, the structural basis of APOBEC3A's preference for YTCD motifs (Y = T, C; D = A, G, T) is explained. The nuclease-resistant phosphorothioated derivatives of these inhibitors have nanomolar potency in vitro and block APOBEC3A activity in human cells. These inhibitors may be useful probes for studying APOBEC3A activity in cellular systems and leading toward, potentially as conjuvants, next-generation, combinatorial anti-mutator and anti-cancer therapies.
PubMed: 37821454
DOI: 10.1038/s41467-023-42174-w
主引用文献が同じPDBエントリー
実験手法
X-RAY DIFFRACTION (1.912 Å)
構造検証レポート
Validation report summary of 8fik
検証レポート(詳細版)ダウンロードをダウンロード

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件を2024-12-18に公開中

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