NSP15 recognizes uracil and cleaves single stranded RNA through an Mn 2+ requiring transesterification reaction . Recent studies indicate that NSP15 is not required for viral RNA synthesis; rather, NSP15 suppresses the host protective immune response through evasion of host dsRNA sensors . Most recently, NSP15 was reported to participate in viral RNA processing by degrading viral polyuridine sequences. This may prevent the host immune sensing system from detecting viral RNA via cell pathogen-recognition receptors, which subsequently inhibits both direct and indirect antiviral effects . These mechanisms are important for normal coronavirus infection of host cells. In the absence of NSP15 activity, viral replication is slowed significantly, and therefore NSP15 remains an attractive target for addressing SARS-CoV-2 infection . NSP15 is only active as a hexamer, which is formed as a dimer of trimers. The NSP15 monomer contains three domains: a N-terminal domain responsible for oligomerization, a middle domain, and a C-terminal domain, which contains the catalytic domain . Binding sites of each of the catalytic domains are accessible despite hexamerization. A recent publication showed the first two crystal structures of SARS-CoV-2 NSP15 with 1.90 Å and 2.20 Å resolution . In the Cterminal catalytic domain of SARS-CoV-2 NSP15, the active site carries six key residues: His235, His250, Lys290, Thr341, Tyr343, and Ser294. Among of these residues, His235, His250, and Lys290 are suggested to constitute the catalytic triad for its nuclease activity. His250 acts as a general base to activate the 2'-OH of the ribose while His235 functions as a general acid to donate a proton to the leaving 5'-OH the ribose . Ser294 together with Tyr343 determine uridine specificity. Ser294 is a key residue to recognize uracil and is assumed to interact with the carbonyl oxygen atom O2 of uracil, while Tyr343 orients the ribose of uridine for cleavage by van-der-Waals interactions . In the crystal structure of the NSP15 citrate-bound form, the citrate ion forms hydrogen bonds with active site residues including His235, His250, Lys290, and Thr341 6 . In the crystal structure of NSP15 complexed with uridine-5'-monophosphate (5'-UMP), 5'-UMP was found to interact with all six active site residues. The uridine base of 5'-UMP interacts with Tyr343 through van der Waals and forms hydrogen bonds with the nitrogen atom of Ser294, Lys290, and His250 . This structural information is important for exploring binding of uridine analogues as a potential SARS-CoV-2 NSP15 inhibitors.