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The crystal structure of the herpes virus ICP8 protein in complex with single-stranded DNA reveals the molecular determinants of nucleotide recognition.

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Title: The crystal structure of the herpes virus ICP8 protein in complex with single-stranded DNA reveals the molecular determinants of nucleotide recognition.
Authors: Erlandsen, Heidi1, Krucinska, Jolanta1, Wilderman, P. Ross2, Makkay, Andrea M.2, Szczepaniak, Renata2, Wright, Lee R.1, Weller, Sandra K.2 Weller@UCHC.edu, Wright, Dennis L.1 Dennis.Wright@UConn.edu
Source: Journal of Biological Chemistry. May2026, Vol. 302 Issue 5, p1-20. 20p.
Subjects: Single-stranded DNA, DNA-protein interactions, DNA replication, Zinc-finger proteins, DNA-binding proteins, Crystal structure, Herpesviruses
Abstract: The HSV-1 single-strand annealing protein ICP8 (UL29) is essential for viral DNA replication and recombination. Although its overall architecture has been described, the molecular basis of single-stranded DNA (ssDNA) recognition was unknown. We report crystal structures of C-terminally truncated ICP8 (ICP8Δ60) bound to poly(dT)25 or poly(dA)25 ssDNA at 3.0 to 3.1 Å resolution, along with higher-resolution apo structures of surface-entropy–reduction variants. ssDNA binds within the neck region between the head and shoulder domains, contacting conserved OB-fold residues via basespecific hydrogen bonds, π-stacking and phosphate backbone interactions. In the poly(dT)25 complex, coordination of a Zn2+ ion stabilizes the zinc finger motif; whereas, in the poly(dA)25 complex, Zn2+ displacement promotes disulfide bond formation that effectively locks the protein into an altered conformation. Microscale thermophoresis and label-free differential scanning fluorimetry reveal a strong preference for pyrimidine-rich sequences, with nanomolar affinity for poly(dT)25 and micromolar for poly(dA)25. Structural modeling identified Y543, R576, R772, R793, Y988, and F998 as key DNA-contact residues. Alanine substitutions caused severe replication defects, particularly for R772A, Y988A, and F998A. ssDNA binding induces ∼26 Å displacement and ∼35 degree rotation of the C-terminal domain and ordering of flexible loops, suggesting a mechanism for cooperative filament assembly. These structures define the molecular determinants of ICP8–ssDNA recognition, reveal thymidine bias and provide a framework for targeting ICP8-mediated functions in herpesvirus replication. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: The crystal structure of the herpes virus ICP8 protein in complex with single-stranded DNA reveals the molecular determinants of nucleotide recognition.
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  Data: <searchLink fieldCode="AR" term="%22Erlandsen%2C+Heidi%22">Erlandsen, Heidi</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Krucinska%2C+Jolanta%22">Krucinska, Jolanta</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Wilderman%2C+P%2E+Ross%22">Wilderman, P. Ross</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Makkay%2C+Andrea+M%2E%22">Makkay, Andrea M.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Szczepaniak%2C+Renata%22">Szczepaniak, Renata</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Wright%2C+Lee+R%2E%22">Wright, Lee R.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Weller%2C+Sandra+K%2E%22">Weller, Sandra K.</searchLink><relatesTo>2</relatesTo><i> Weller@UCHC.edu</i><br /><searchLink fieldCode="AR" term="%22Wright%2C+Dennis+L%2E%22">Wright, Dennis L.</searchLink><relatesTo>1</relatesTo><i> Dennis.Wright@UConn.edu</i>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. May2026, Vol. 302 Issue 5, p1-20. 20p.
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  Data: <searchLink fieldCode="DE" term="%22Single-stranded+DNA%22">Single-stranded DNA</searchLink><br /><searchLink fieldCode="DE" term="%22DNA-protein+interactions%22">DNA-protein interactions</searchLink><br /><searchLink fieldCode="DE" term="%22DNA+replication%22">DNA replication</searchLink><br /><searchLink fieldCode="DE" term="%22Zinc-finger+proteins%22">Zinc-finger proteins</searchLink><br /><searchLink fieldCode="DE" term="%22DNA-binding+proteins%22">DNA-binding proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Crystal+structure%22">Crystal structure</searchLink><br /><searchLink fieldCode="DE" term="%22Herpesviruses%22">Herpesviruses</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: The HSV-1 single-strand annealing protein ICP8 (UL29) is essential for viral DNA replication and recombination. Although its overall architecture has been described, the molecular basis of single-stranded DNA (ssDNA) recognition was unknown. We report crystal structures of C-terminally truncated ICP8 (ICP8Δ60) bound to poly(dT)25 or poly(dA)25 ssDNA at 3.0 to 3.1 Å resolution, along with higher-resolution apo structures of surface-entropy–reduction variants. ssDNA binds within the neck region between the head and shoulder domains, contacting conserved OB-fold residues via basespecific hydrogen bonds, π-stacking and phosphate backbone interactions. In the poly(dT)25 complex, coordination of a Zn2+ ion stabilizes the zinc finger motif; whereas, in the poly(dA)25 complex, Zn2+ displacement promotes disulfide bond formation that effectively locks the protein into an altered conformation. Microscale thermophoresis and label-free differential scanning fluorimetry reveal a strong preference for pyrimidine-rich sequences, with nanomolar affinity for poly(dT)25 and micromolar for poly(dA)25. Structural modeling identified Y543, R576, R772, R793, Y988, and F998 as key DNA-contact residues. Alanine substitutions caused severe replication defects, particularly for R772A, Y988A, and F998A. ssDNA binding induces ∼26 Å displacement and ∼35 degree rotation of the C-terminal domain and ordering of flexible loops, suggesting a mechanism for cooperative filament assembly. These structures define the molecular determinants of ICP8–ssDNA recognition, reveal thymidine bias and provide a framework for targeting ICP8-mediated functions in herpesvirus replication. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
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      – Type: doi
        Value: 10.1016/j.jbc.2026.111366
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      – Code: eng
        Text: English
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        PageCount: 20
        StartPage: 1
    Subjects:
      – SubjectFull: Single-stranded DNA
        Type: general
      – SubjectFull: DNA-protein interactions
        Type: general
      – SubjectFull: DNA replication
        Type: general
      – SubjectFull: Zinc-finger proteins
        Type: general
      – SubjectFull: DNA-binding proteins
        Type: general
      – SubjectFull: Crystal structure
        Type: general
      – SubjectFull: Herpesviruses
        Type: general
    Titles:
      – TitleFull: The crystal structure of the herpes virus ICP8 protein in complex with single-stranded DNA reveals the molecular determinants of nucleotide recognition.
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              M: 05
              Text: May2026
              Type: published
              Y: 2026
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