5CQD

Crystal Structure of the Cancer Genomic DNA Mutator APOBEC3B

5CQD の概要

• エントリーDOI: 10.2210/pdb5cqd/pdb
• 関連するPDBエントリー: 5CQH 5CQI 5CQK
• 分子名称: DNA dC->dU-editing enzyme APOBEC-3B, ZINC ION, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: apobec, deaminase, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 44549.21

構造登録者

Shi, K.,Kurahashi, K.,Aihara, H. (登録日: 2015-07-21, 公開日: 2015-10-07, 最終更新日: 2023-09-27)

主引用文献

Shi, K.,Carpenter, M.A.,Kurahashi, K.,Harris, R.S.,Aihara, H.
Crystal Structure of the DNA Deaminase APOBEC3B Catalytic Domain.
J.Biol.Chem., 290:28120-28130, 2015

PubMed Abstract: Functional and deep sequencing studies have combined to demonstrate the involvement of APOBEC3B in cancer mutagenesis. APOBEC3B is a single-stranded DNA cytosine deaminase that functions normally as a nuclear-localized restriction factor of DNA-based pathogens. However, it is overexpressed in cancer cells and elicits an intrinsic preference for 5'-TC motifs in single-stranded DNA, which is the most frequently mutated dinucleotide in breast, head/neck, lung, bladder, cervical, and several other tumor types. In many cases, APOBEC3B mutagenesis accounts for the majority of both dispersed and clustered (kataegis) cytosine mutations. Here, we report the first structures of the APOBEC3B catalytic domain in multiple crystal forms. These structures reveal a tightly closed active site conformation and suggest that substrate accessibility is regulated by adjacent flexible loops. Residues important for catalysis are identified by mutation analyses, and the results provide insights into the mechanism of target site selection. We also report a nucleotide (dCMP)-bound crystal structure that informs a multistep model for binding single-stranded DNA. Overall, these high resolution crystal structures provide a framework for further mechanistic studies and the development of novel anti-cancer drugs to inhibit this enzyme, dampen tumor evolution, and minimize adverse outcomes such as drug resistance and metastasis.

PubMed: 26416889
DOI: 10.1074/jbc.M115.679951

実験手法

X-RAY DIFFRACTION (2.08 Å)