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Structural understanding of non-nucleoside inhibition in an elongating herpesvirus polymerase

Author

Listed:
  • Robert P. Hayes

    (Computational and Structural Chemistry, Merck & Co., Inc.)

  • Mee Ra Heo

    (Computational and Structural Chemistry, Merck & Co., Inc.)

  • Mark Mason

    (Computational and Structural Chemistry, Merck & Co., Inc.)

  • John Reid

    (Computational and Structural Chemistry, Merck & Co., Inc.)

  • Christine Burlein

    (Quantitative Biosciences, Merck & Co., Inc.)

  • Kira A. Armacost

    (Computational and Structural Chemistry, Merck & Co., Inc.)

  • David M. Tellers

    (Discovery Chemistry, Merck & Co., Inc.)

  • Izzat Raheem

    (Discovery Chemistry, Merck & Co., Inc.)

  • Anthony W. Shaw

    (Discovery Chemistry, Merck & Co., Inc.)

  • Edward Murray

    (Infectious Diseases and Vaccines, Merck & Co., Inc.)

  • Philip M. McKenna

    (Infectious Diseases and Vaccines, Merck & Co., Inc.)

  • Pravien Abeywickrema

    (Computational and Structural Chemistry, Merck & Co., Inc.)

  • Sujata Sharma

    (Computational and Structural Chemistry, Merck & Co., Inc.)

  • Stephen M. Soisson

    (Computational and Structural Chemistry, Merck & Co., Inc.)

  • Daniel Klein

    (Computational and Structural Chemistry, Merck & Co., Inc.)

Abstract

All herpesviruses encode a conserved DNA polymerase that is required for viral genome replication and serves as an important therapeutic target. Currently available herpesvirus therapies include nucleoside and non-nucleoside inhibitors (NNI) that target the DNA-bound state of herpesvirus polymerase and block replication. Here we report the ternary complex crystal structure of Herpes Simplex Virus 1 DNA polymerase bound to DNA and a 4-oxo-dihydroquinoline NNI, PNU-183792 (PNU), at 3.5 Å resolution. PNU bound at the polymerase active site, displacing the template strand and inducing a conformational shift of the fingers domain into an open state. These results demonstrate that PNU inhibits replication by blocking association of dNTP and stalling the enzyme in a catalytically incompetent conformation, ultimately acting as a nucleotide competing inhibitor (NCI). Sequence conservation of the NCI binding pocket further explains broad-spectrum activity while a direct interaction between PNU and residue V823 rationalizes why mutations at this position result in loss of inhibition.

Suggested Citation

  • Robert P. Hayes & Mee Ra Heo & Mark Mason & John Reid & Christine Burlein & Kira A. Armacost & David M. Tellers & Izzat Raheem & Anthony W. Shaw & Edward Murray & Philip M. McKenna & Pravien Abeywickr, 2021. "Structural understanding of non-nucleoside inhibition in an elongating herpesvirus polymerase," Nature Communications, Nature, vol. 12(1), pages 1-7, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23312-8
    DOI: 10.1038/s41467-021-23312-8
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