7UXD

Crystal structure of APOBEC3G Catalytic domain complex with ssDNA containing 2'-deoxy Zebularine.

7UXD の概要

• エントリーDOI: 10.2210/pdb7uxd/pdb
• 分子名称: DNA dC->dU-editing enzyme APOBEC-3G, DNA (5'-D(*AP*AP*TP*CP*CP*(DDN)P*AP*AP*A)-3'), ZINC ION, ... (4 entities in total)
• 機能のキーワード: dna cytidine deaminase, apobec, apobec- inhibitor complex, zebularine, hydrolase-dna complex, hydrolase/dna
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 25881.35

構造登録者

Maiti, A.,Matsuo, H. (登録日: 2022-05-05, 公開日: 2022-12-14, 最終更新日: 2023-10-25)

主引用文献

Maiti, A.,Hedger, A.K.,Myint, W.,Balachandran, V.,Watts, J.K.,Schiffer, C.A.,Matsuo, H.
Structure of the catalytically active APOBEC3G bound to a DNA oligonucleotide inhibitor reveals tetrahedral geometry of the transition state.
Nat Commun, 13:7117-7117, 2022

PubMed Abstract: APOBEC3 proteins (A3s) are enzymes that catalyze the deamination of cytidine to uridine in single-stranded DNA (ssDNA) substrates, thus playing a key role in innate antiviral immunity. However, the APOBEC3 family has also been linked to many mutational signatures in cancer cells, which has led to an intense interest to develop inhibitors of A3's catalytic activity as therapeutics as well as tools to study A3's biochemistry, structure, and cellular function. Recent studies have shown that ssDNA containing 2'-deoxy-zebularine (dZ-ssDNA) is an inhibitor of A3s such as A3A, A3B, and A3G, although the atomic determinants of this activity have remained unknown. To fill this knowledge gap, we determined a 1.5 Å resolution structure of a dZ-ssDNA inhibitor bound to active A3G. The crystal structure revealed that the activated dZ-HO mimics the transition state by coordinating the active site Zn and engaging in additional stabilizing interactions, such as the one with the catalytic residue E259. Therefore, this structure allowed us to capture a snapshot of the A3's transition state and suggests that developing transition-state mimicking inhibitors may provide a new opportunity to design more targeted molecules for A3s in the future.

PubMed: 36402773
DOI: 10.1038/s41467-022-34752-1

実験手法

X-RAY DIFFRACTION (1.5 Å)