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Varicella zoster virus (VZV) is a highly infectious human herpesvirus that is the causative agent for chicken pox and shingles. VZV encodes a functional thymidylate synthase (TS), which is the sole enzyme that produces dTMP from dUMP  de novo . To study substrate binding, the complex structure of TS VZV  with dUMP was determined to a resolution of 2.9 Å. In the absence of a folate co-substrate, dUMP binds in the conserved TS active site and is coordinated similarly as in the human encoded TS (TS HS ) in an open conformation. The interactions between TS VZV  with dUMP and a cofactor analog, raltitrexed, were also studied using differential scanning fluorimetry (DSF), suggesting that TS VZV  binds dUMP and raltitrexed in a sequential binding mode like other TS. The DSF also revealed interactions between TS VZV  and  in vitro  phosphorylated brivudine (BVDU P ), a highly potent anti-herpesvirus drug against VZV infections. The binding of BVDU P  to TS VZV  was further confirmed by the complex structure of TS VZV  and BVDU P  solved at a resolution of 2.9 Å. BVDU P  binds similarly as dUMP in the TS HS  but it induces a closed conformation of the active site. The structure supports that the 5-bromovinyl substituent on BVDU P  is likely to inhibit TS VZV  by preventing the transfer of a methylene group from its cofactor and the subsequent formation of dTMP. The interactions between TS VZV  and BVDU P  are consistent with that TS VZV  is indeed a target of brivudine  in vivo . The work also provided the structural basis for rational design of more specific TS VZV  inhibitors.

plos one

Structure of the Varicella Zoster Virus Thymidylate Synthase Establishes Functional and Structural Similarities as the Human Enzyme and Potentiates Itself as a Target of Brivudine