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-Structure paper
| タイトル | Activity and structure of human (d)CTP deaminase CDADC1. |
|---|---|
| ジャーナル・号・ページ | Proc Natl Acad Sci U S A, Vol. 122, Issue 19, Page e2424245122, Year 2025 |
| 掲載日 | 2025年5月13日 |
著者 | Anton Slyvka / Ishan Rathore / Renbin Yang / Olga Gewartowska / Tapan Kanai / George T Lountos / Krzysztof Skowronek / Mariusz Czarnocki-Cieciura / Alexander Wlodawer / Matthias Bochtler / ![]() |
| PubMed 要旨 | Vertebrates have evolved an understudied protein termed CDADC1 (NYD-SP15) that contains an inactive N-terminal and active C-terminal DCTD-like domain. Here, we show that human CDADC1 is a (d)CTP- ...Vertebrates have evolved an understudied protein termed CDADC1 (NYD-SP15) that contains an inactive N-terminal and active C-terminal DCTD-like domain. Here, we show that human CDADC1 is a (d)CTP-specific deaminase, with a roughly 2-fold in vitro preference for dCTP over CTP. We determined high-resolution cryo-EM structures of CDADC1 in the absence of substrate and in complex with dCTP and 5-methyl-dCTP. The structures show that CDADC1 forms trimers and dimers of trimers in solution. The (d)CTP substrate is selected by a narrow pocket for the cytosine base and multiple lysine and arginine contacts to the triphosphate. Substrate binding promotes the association of trimers into hexamers and the transition of the hexamers from a loose to a tighter arrangement. Genetic experiments in mice show that loss of Cdadc1 is surprisingly well tolerated, even in the absence of the dCMP deaminase Dctd that is considered as the main source of dUMP, the precursor of dTTP. |
リンク | Proc Natl Acad Sci U S A / PubMed:40324085 / PubMed Central |
| 手法 | EM (単粒子) |
| 解像度 | 2.8 - 3.7 Å |
| 構造データ | EMDB-52121, PDB-9hfq: EMDB-52122, PDB-9hfr: ![]() EMDB-52123: Cryo-EM structure of human CDADC1 inactive mutant (E400A): trimer in the presence of dCTP in solution (not bound) EMDB-52124, PDB-9hfs: ![]() EMDB-52125: Cryo-EM structure of human CDADC1 inactive mutant (E400A): trimer in the presence of 5mdCTP in solution (not bound) EMDB-52126, PDB-9hft: |
| 化合物 | ![]() ChemComp-ZN: ![]() ChemComp-HOH: ![]() ChemComp-DCP: ![]()
PDB-1i2i: CRYSTAL STRUCTURE OF SALMONELLA TYPHIMURIUM OMP SYNTHASE IN COMPLEX WITH MGPRPP AND OROTATE |
| 由来 |
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キーワード | HYDROLASE / Human dCTP deaminase / trimer / Zinc-dependent / Nucleotide metabolism |
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homo sapiens (ヒト)
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