The herpes simplex origin-binding protein: mechanisms for sequence-specific DNA binding and dimerization revealed by...

Area of Science:

• Structural Biology
• Virology
• Drug Discovery

Background:

• Herpes simplex viruses (HSV-1,2) are increasingly resistant to current antiviral therapies.
• The HSV-1 origin-binding protein (OBP), a DNA helicase, is a potential target for new antiviral drugs.

Purpose of the Study:

• To determine the structure of HSV-1 OBP in complex with DNA and ATP analogs.
• To elucidate the molecular mechanisms of HSV-1 DNA origin recognition and unwinding.
• To identify potential druggable sites on HSV-1 OBP for antiviral drug development.

Main Methods:

• Cryo-electron microscopy (cryo-EM) at up to 2.8 Å resolution.
• Structural analysis of OBP in multiple conformational states, including complexes with OriS DNA and ATPγS.
• Investigation of OBP-DNA interactions, including monomer-DNA and dimer-dimer assemblies.

Main Results:

• Revealed an unexpected head-to-tail OBP dimer structure stabilized by the C-terminal domain.
• Identified the RVKNL motif as crucial for sequence-specific DNA recognition.
• Uncovered potential regulatory interactions between OBP and ICP8.
• Observed OBP monomer bound to a DNA hairpin and a dimer-dimer assembly bound to DNA.

Conclusions:

• The structures provide molecular insights into HSV-1 origin recognition and unwinding.
• Identified multiple druggable interfaces on OBP for structure-based antiviral design.
• Paves the way for developing novel antivirals against drug-resistant HSV-1 infections.