Shankar, Sundaresh, Pan, Junhua, Yang, Pan et al. (9 more authors) (2024) Viral DNA polymerase structures reveal mechanisms of antiviral drug resistance. Cell. ISSN 1097-4172
Abstract
DNA polymerases are important drug targets, and many structural studies have captured them in distinct conformations. However, a detailed understanding of the impact of polymerase conformational dynamics on drug resistance is lacking. We determined cryoelectron microscopy (cryo-EM) structures of DNA-bound herpes simplex virus polymerase holoenzyme in multiple conformations and interacting with antivirals in clinical use. These structures reveal how the catalytic subunit Pol and the processivity factor UL42 bind DNA to promote processive DNA synthesis. Unexpectedly, in the absence of an incoming nucleotide, we observed Pol in multiple conformations with the closed state sampled by the fingers domain. Drug-bound structures reveal how antivirals may selectively bind enzymes that more readily adopt the closed conformation. Molecular dynamics simulations and the cryo-EM structure of a drug-resistant mutant indicate that some resistance mutations modulate conformational dynamics rather than directly impacting drug binding, thus clarifying mechanisms that drive drug selectivity.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 The Author(s) |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) |
Depositing User: | Pure (York) |
Date Deposited: | 25 Sep 2024 12:00 |
Last Modified: | 21 Nov 2024 00:50 |
Published Version: | https://doi.org/10.1016/j.cell.2024.07.048 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1016/j.cell.2024.07.048 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:217625 |
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Description: Viral DNA polymerase structures reveal mechanisms of antiviral drug resistance
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