8IS4

Structure of an Isocytosine specific deaminase Vcz in complexed with 5-FU

8IS4 の概要

• エントリーDOI: 10.2210/pdb8is4/pdb
• 関連するPDBエントリー: 7ww2
• 分子名称: Hydroxydechloroatrazine ethylaminohydrolase, 5-FLUOROURACIL, ZINC ION, ... (6 entities in total)
• 機能のキーワード: isocytosine, deaminase, vcz, 5-fu, hydrolase
• 由来する生物種: Obesumbacterium proteus
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 99693.93

構造登録者

Guo, W.T.,Li, X.J.,Wu, B.X. (登録日: 2023-03-20, 公開日: 2023-08-30, 最終更新日: 2024-11-20)

主引用文献

Guo, W.,Li, X.,Fan, J.,Li, H.,Wen, Y.,Meng, C.,Chen, H.,Zhao, Z.,Zhang, Y.,Du, Y.,Wu, B.
Structural characterization of an isocytosine-specific deaminase VCZ reveals its application potential in the anti-cancer therapy.
Iscience, 26:107672-107672, 2023

PubMed Abstract: Non-natural nucleobase isocytosine (IC) is the isomer of cytosine; its chemical derivate 5-fluoroisocytosine (5-FIC) together with the isocytosine-specific deaminase (ICD) VCZ was suggested to be potential practical enzyme/prodrug pair for cancer therapy through gene-directed enzyme-prodrug therapy (GDEPT) method. In this study, we have determined the crystal structures of apo-VCZ and its complex with 5-FU. We identified the critical residues for substrate binding and catalytic reaction. We also captured the substrate-induced conformational changes of VCZ, then proposed the conjectural reaction procedures of VCZ for converting the IC into the uracil. Moreover, we evaluated the therapeutic effect of wildtype or the mutated VCZ protein in the colorectal cancer cell lines. Our studies will shed light on optimizing the ICD/5-FIC pairs by modifying either the enzyme or the prodrug based on the structural observations, thereby improving the possibility of applying the ICD/5-FIC pair in clinical trials.

PubMed: 37680460
DOI: 10.1016/j.isci.2023.107672

実験手法

X-RAY DIFFRACTION (1.9 Å)