Mutations in SAM domain and HD domain containing protein 1 (SAMHD1) are found in a neuro-developmental disorder, Aicardi-Gouti&#
xe8;res Syndrome (AGS) and cancers, and SAMHD1, which is a dNTP tri-phosphorylase, was identified as a myeloid specific HIV-1 restriction factor. Here, we characterized the enzymology and structure of a SAMHD1 ortholog of C. elegans, ZK177.8, which also reportedly induces developmental defects upon gene knockdown. We found ZK177.8 protein is a dNTPase allosterically regulated by dGTP. The active site of ZK177.8 recognizes both 2' OH and tri-phosphate moieties of dNTPs, but not base moiety. The dGTP activator induces the formation of the enzymatically active ZK177.8 tetramers, and ZK177.8 protein lowers cellular dNTP levels in a human monocytic cell line. Finally, ZK177.8 tetramers display very similar X-ray crystal structure with human and mouse SAMHD1s except its lack of the canonical SAM domain. This striking conservation in structure, function and allosteric regulatory mechanism for the hydrolysis of the DNA building blocks supports their host developmental roles.