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
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 TSVZ...
| Main Authors: | , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2016
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| Online Access: | https://hdl.handle.net/10356/82348 http://hdl.handle.net/10220/39978 |
| _version_ | 1811688041546252288 |
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| author | Hew, Kelly Dahlroth, Sue-Li Veerappan, Saranya Pan, Lucy Xin Cornvik, Tobias Nordlund, Pär |
| author2 | Roujeinikova, Anna |
| author_facet | Roujeinikova, Anna Hew, Kelly Dahlroth, Sue-Li Veerappan, Saranya Pan, Lucy Xin Cornvik, Tobias Nordlund, Pär |
| author_sort | Hew, Kelly |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T05:25:54Z |
| format | Journal Article |
| id | ntu-10356/82348 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:25:54Z |
| publishDate | 2016 |
| record_format | dspace |
| spelling | ntu-10356/823482023-02-28T17:03:18Z 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 Hew, Kelly Dahlroth, Sue-Li Veerappan, Saranya Pan, Lucy Xin Cornvik, Tobias Nordlund, Pär Roujeinikova, Anna School of Biological Sciences fluorometry drug targeting 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. Published version 2016-02-15T08:10:30Z 2019-12-06T14:53:49Z 2016-02-15T08:10:30Z 2019-12-06T14:53:49Z 2015 Journal Article Hew, K., Dahlroth, S.-L., Veerappan, S., Pan, L. X., Cornvik, T., & Nordlund, P. (2015). 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(12), e0143947-. 1932-6203 https://hdl.handle.net/10356/82348 http://hdl.handle.net/10220/39978 10.1371/journal.pone.0143947 26630264 en PLOS ONE © 2015 Hew et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 16 p. application/pdf |
| spellingShingle | fluorometry drug targeting Hew, Kelly Dahlroth, Sue-Li Veerappan, Saranya Pan, Lucy Xin Cornvik, Tobias Nordlund, Pär 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 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | fluorometry drug targeting |
| url | https://hdl.handle.net/10356/82348 http://hdl.handle.net/10220/39978 |
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