Crystal structure and functional implications of cyclic di-pyrimidine-synthesizing cGAS/DncV-like nucleotidyltransferases

Chia-Shin Yang, Tzu-Ping Ko, Chao-Jung Chen, Mei-Hui Hou, Yu-Chuan Wang and Yeh Chen ()
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Chia-Shin Yang: Genomics BioSci & Tech Co. Ltd.
Tzu-Ping Ko: Institute of Biological Chemistry, Academia Sinica
Chao-Jung Chen: China Medical University
Mei-Hui Hou: Genomics BioSci & Tech Co. Ltd.
Yu-Chuan Wang: Trade Wind Biotech Co. Ltd.
Yeh Chen: National Chung Hsing University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Purine-containing nucleotide second messengers regulate diverse cellular activities. Cyclic di-pyrimidines mediate anti-phage functions in bacteria; however, the synthesis mechanism remains elusive. Here, we determine the high-resolution structures of cyclic di-pyrimidine-synthesizing cGAS/DncV-like nucleotidyltransferases (CD-NTases) in clade E (CdnE) in its apo, substrate-, and intermediate-bound states. A conserved (R/Q)xW motif controlling the pyrimidine specificity of donor nucleotide is identified. Mutation of Trp or Arg from the (R/Q)xW motif to Ala rewires its specificity to purine nucleotides, producing mixed purine-pyrimidine cyclic dinucleotides (CDNs). Preferential binding of uracil over cytosine bases explains the product specificity of cyclic di-pyrimidine-synthesizing CdnE to cyclic di-UMP (cUU). Based on the intermediate-bound structures, a synthetic pathway for cUU containing a unique 2’3’-phosphodiester linkage through intermediate pppU[3’−5’]pU is deduced. Our results provide a framework for pyrimidine selection and establish the importance of conserved residues at the C-terminal loop for the specificity determination of CD-NTases.

Date: 2023
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DOI: 10.1038/s41467-023-40787-9

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