Secondary Structure and Structure-Activity Relationships of Peptides Corresponding to the Subunit Interface of Herpes Simplex Virus DNA Polymerase

• Published in: The Journal of biological chemistry Vol. 275; no. 1; pp. 472 - 478
• Main Authors: Bridges, Kristie Grove, Hua, Qingxin, Brigham-Burke, Michael R., Martin, John D., Hensley, Preston, Dahl, Charles E., Digard, Paul, Weiss, Michael A., Coen, Donald M.
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 07.01.2000
• Subjects: Amino Acid Sequence; Cold Temperature; DNA-Directed DNA Polymerase - chemistry; DNA-Directed DNA Polymerase - genetics; DNA-Directed DNA Polymerase - metabolism; Exodeoxyribonucleases; Herpes simplex virus; Herpesvirus 1, Human - enzymology; Molecular Sequence Data; Nuclear Magnetic Resonance, Biomolecular; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - metabolism; Protein Binding; Protein Structure, Secondary; Structure-Activity Relationship; UL42 protein; Ultracentrifugation; Viral Proteins - chemistry; Viral Proteins - genetics; Viral Proteins - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.275.1.472

The interaction of the catalytic subunit of herpes simplex virus DNA polymerase with the processivity subunit, UL42, is essential for viral replication and is thus a potential target for antiviral drug discovery. We have previously reported that a peptide analogous to the C-terminal 36 residues of the catalytic subunit, which are necessary and sufficient for its interaction with UL42, forms a monomeric structure with partial α-helical character. This peptide and one analogous to the C-terminal 18 residues specifically inhibit UL42-dependent long chain DNA synthesis. Using multidimensional 1 H nuclear magnetic resonance spectroscopy, we have found that the 36-residue peptide contains partially ordered N- and C-terminal α-helices separated by a less ordered region. A series of “alanine scan” peptides derived from the C-terminal 18 residues of the catalytic subunit were tested for their ability to inhibit long-chain DNA synthesis and by circular dichroism for secondary structure. The results identify structural aspects and specific side chains that appear to be crucial for interacting with UL42. These findings may aid in the rational design of new drugs for the treatment of herpesvirus infections.