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Open AccessFeature PaperArticle

Hinge Region in DNA Packaging Terminase pUL15 of Herpes Simplex Virus: A Potential Allosteric Target for Antiviral Drugs

1
Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA
2
Center for Computation & Technology, Louisiana State University, Baton Rouge, LA 70803, USA
*
Author to whom correspondence should be addressed.
Biomolecules 2019, 9(10), 603; https://doi.org/10.3390/biom9100603
Received: 10 September 2019 / Revised: 30 September 2019 / Accepted: 8 October 2019 / Published: 12 October 2019
(This article belongs to the Special Issue 2019 Feature Papers by Biomolecules’ Editorial Board Members)
Approximately 80% of adults are infected with a member of the herpesviridae family. Herpesviruses establish life-long latent infections within neurons, which may reactivate into lytic infections due to stress or immune suppression. There are nine human herpesviruses (HHV) posing health concerns from benign conditions to life threatening encephalitis, including cancers associated with viral infections. The current treatment options for most HHV conditions mainly include several nucleoside and nucleotide analogs targeting viral DNA polymerase. Although these drugs help manage infections, their common mechanism of action may lead to the development of drug resistance, which is particularly devastating in immunocompromised patients. Therefore, new classes of drugs directed against novel targets in HHVs are necessary to alleviate this issue. We analyzed the conservation rates of all proteins in herpes simplex virus 1 (HHV-1), a representative of the HHV family and one of the most common viruses infecting the human population. Furthermore, we generated a full-length structure model of the most conserved HHV-1 protein, the DNA packaging terminase pUL15. A series of computational analyses were performed on the model to identify ATP and DNA binding sites and characterize the dynamics of the protein. Our study indicates that proteins involved in HHV-1 DNA packaging and cleavage are amongst the most conserved gene products of HHVs. Since the packaging protein pUL15 is the most conserved among all HHV-1 gene products, the virus will have a lower chance of developing resistance to small molecules targeting pUL15. A subsequent analysis of the structure of pUL15 revealed distinct ATP and DNA binding domains and the elastic network model identifies a functionally important hinge region between the two domains of pUL15. The atomic information on the active and allosteric sites in the ATP- and DNA-bound model of pUL15 presented in this study can inform the structure-based drug discovery of a new class of drugs to treat a wide range of HHVs. View Full-Text
Keywords: herpesviruses; herpes simplex virus 1; HHV-1; DNA packaging terminase; pUL15; DNA packaging motor herpesviruses; herpes simplex virus 1; HHV-1; DNA packaging terminase; pUL15; DNA packaging motor
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Thaljeh, L.F.; Rothschild, J.A.; Naderi, M.; Coghill, L.M.; Brown, J.M.; Brylinski, M. Hinge Region in DNA Packaging Terminase pUL15 of Herpes Simplex Virus: A Potential Allosteric Target for Antiviral Drugs. Biomolecules 2019, 9, 603.

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