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Publication Abstract from PubMed

Mpox virus (MPXV) is the etiological agent of mpox, which is a major threat to human health. The identification of potential drug targets and the development of effective antiviral therapies are still urgently needed. The thymidine kinase (TK) encoded by MPXV initiates the deoxythymidine triphosphate (dTTP) salvage synthesis pathway and facilitates viral DNA replication. MPXV without TK presents significant replication defects. MPXV TK is also responsible for the activation of nucleos(t)ide analogs, which are an important class of antivirals. Despite its importance in the viral life cycle and antiviral development, the structure and catalytic mechanism of MPXV TK are not fully understood. Here, we determined the three-dimensional structure of an MPXV TK variant, in which the glutamic acid at position 83 was substituted with alanine. MPXV TK consists of two domains and forms a tetramer. One protomer binds dTTP with two lassos and a P-loop, while the other protomers are captured in apo-form. Mutation of residues near the dTTP-binding site significantly reduces the catalytic activity of MPXV TK, indicating the importance of these residues in substrate binding and/or catalysis. Specifically, E83 is found to play a crucial role in stabilizing dTTP and lasso II. A biochemical assay confirmed that dTTP functions as a feedback inhibitor of MPXV TK and its inhibitory potency was evaluated. These results may facilitate the discovery of specific inhibitors targeting TK to mitigate MPXV infections.

Structural and mechanistic insight into the phosphorylation reaction catalyzed by mpox virus thymidine kinase.,Zhang T, Chen X, Tao C, Huang H, Luo Z, Liu M, Cui W, Wang W Antiviral Res. 2025 Feb 26;237:106125. doi: 10.1016/j.antiviral.2025.106125. PMID:40020877^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.