Evidence map›Paper›PMID 39197451›Full record

ArticleCell2024

Viral DNA polymerase structures reveal mechanisms of antiviral drug resistance.

Sundaresh Shankar, Junhua Pan, Pan Yang, Yuemin Bian, Gábor Oroszlán, Zishuo Yu, Purba Mukherjee, David J Filman, James M Hogle, Mrinal Shekhar and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.

0numbers the graph read from it
0cells of the map it votes in
25citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

25 citing papers in PubMed.

  1. Article
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  4. Review
  5. Article
  6. Article
  7. RSC chemical biology · 2026
    Article
  8. Article
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  16. Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Sundaresh ShankarDepartment of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
Junhua PanDepartment of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Biomedical Research Institute and School of Life and Health Sciences, Hubei University of Technology, Wuhan, Hubei, China.
Pan YangDepartment of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
Yuemin BianSchool of Medicine, Shanghai University, Shanghai, China; Center for the Development of Therapeutics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Gábor OroszlánDepartment of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
Zishuo YuDepartment of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
Purba MukherjeeDepartment of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; York Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York, UK.
David J FilmanDepartment of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
James M HogleDepartment of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
Mrinal ShekharCenter for the Development of Therapeutics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Donald M CoenDepartment of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
Jonathan AbrahamDepartment of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA; Center for Integrated Solutions in Infectious Diseases, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: jonathan_abraham@hms.harvard.edu.

Funding

MOLECULAR GENETICS OF HSV DNA POLYMERASE GENER01AI019838 · NIAID · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI COEN, DONALD M, HOGLE, JAMES M · 1985 to 2015
$5.9M
Structural studies of herpesvirus DNA polymerasesR21AI141940 · NIAID · HARVARD MEDICAL SCHOOL · PI ABRAHAM, JONATHAN, COEN, DONALD M · 2019 to 2020
$466k
NIAID NIH HHS R01 AI019838NIAID NIH HHS R21 AI141940
6 · The paper itself

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.

Indexed as

Antiviral AgentsCryoelectron MicroscopyDNA-Directed DNA PolymeraseDrug Resistance, ViralMolecular Dynamics SimulationViral ProteinsDNA, ViralExodeoxyribonucleasesHumansAntiviral AgentsDNA-Directed DNA PolymeraseDNA polymerase, SimplexvirusDNA, ViralExodeoxyribonucleasesViral Proteinsacyclovirconformational dynamicscryo-EMDNA polymerasedrug resistancefoscarnetherpesvirus

Identifiers

PMID39197451
PMCPMC11787825

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.