9HFT

Cryo-EM structure of human CDADC1 inactive mutant (E400A): hexamer with 5mdCTP bound in the active site

This is a non-PDB format compatible entry.

Summary for 9HFT

• Entry DOI: 10.2210/pdb9hft/pdb
• Related: 9HFQ 9HFR 9HFS
• EMDB information: 52121 52122 52123 52124 52125 52126
• Descriptor: Cytidine and dCMP deaminase domain-containing protein 1, ZINC ION, [[(2~{R},3~{S},5~{R})-5-(4-azanyl-5-methyl-2-oxidanylidene-pyrimidin-1-yl)-3-oxidanyl-oxolan-2-yl]methoxy-oxidanyl-phosphoryl] phosphono hydrogen phosphate, ... (4 entities in total)
• Functional Keywords: human dctp deaminase, trimer, zinc-dependent, nucleotide metabolism, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 6
• Total formula weight: 367585.93

Authors

Slyvka, A.,Rathore, I.,Yang, R.,Kanai, T.,Lountos, G.,Wang, Z.,Skowronek, K.,Czarnocki-Cieciura, M.,Wlodawer, A.,Bochtler, M. (deposition date: 2024-11-18, release date: 2025-04-30, Last modification date: 2025-05-21)

Primary citation

Slyvka, A.,Rathore, I.,Yang, R.,Gewartowska, O.,Kanai, T.,Lountos, G.T.,Skowronek, K.,Czarnocki-Cieciura, M.,Wlodawer, A.,Bochtler, M.
Activity and structure of human (d)CTP deaminase CDADC1.
Proc.Natl.Acad.Sci.USA, 122:e2424245122-e2424245122, 2025

PubMed Abstract: 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.

PubMed: 40324085
DOI: 10.1073/pnas.2424245122

Experimental method

ELECTRON MICROSCOPY (2.9 Å)