4XSD
Complex structure of thymidylate synthase from varicella zoster virus with a dUMP
Summary for 4XSD
| Entry DOI | 10.2210/pdb4xsd/pdb |
| Descriptor | Thymidylate synthase, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE (3 entities in total) |
| Functional Keywords | vzv, thymidylate synthase, herpesvirus, viral protein |
| Biological source | Varicella-zoster virus (strain Oka vaccine) (HHV-3) |
| Total number of polymer chains | 4 |
| Total formula weight | 144308.12 |
| Authors | |
| Primary citation | Hew, K.,Dahlroth, S.L.,Veerappan, S.,Pan, L.X.,Cornvik, T.,Nordlund, P. 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. Plos One, 10:e0143947-e0143947, 2015 Cited by PubMed Abstract: 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 TSVZV 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 (TSHS) in an open conformation. The interactions between TSVZV with dUMP and a cofactor analog, raltitrexed, were also studied using differential scanning fluorimetry (DSF), suggesting that TSVZV binds dUMP and raltitrexed in a sequential binding mode like other TS. The DSF also revealed interactions between TSVZV and in vitro phosphorylated brivudine (BVDUP), a highly potent anti-herpesvirus drug against VZV infections. The binding of BVDUP to TSVZV was further confirmed by the complex structure of TSVZV and BVDUP solved at a resolution of 2.9 Å. BVDUP binds similarly as dUMP in the TSHS but it induces a closed conformation of the active site. The structure supports that the 5-bromovinyl substituent on BVDUP is likely to inhibit TSVZV by preventing the transfer of a methylene group from its cofactor and the subsequent formation of dTMP. The interactions between TSVZV and BVDUP are consistent with that TSVZV is indeed a target of brivudine in vivo. The work also provided the structural basis for rational design of more specific TSVZV inhibitors. PubMed: 26630264DOI: 10.1371/journal.pone.0143947 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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