7LUF

HSV1 polymerase ternary complex with dsDNA and PNU-183792

Summary for 7LUF

• Entry DOI: 10.2210/pdb7luf/pdb
• Descriptor: DNA polymerase, DNA (5'-D(P*AP*TP*GP*GP*TP*AP*GP*GP*GP*GP*AP*AP*GP*GP*AP*TP*CP*G)-3'), DNA (5'-D(*CP*GP*AP*TP*CP*CP*TP*TP*CP*CP*CP*CP*TP*AP*C)-3'), ... (4 entities in total)
• Functional Keywords: herpesvirus, b-family polymerase, nucleotide competing inhibitor, non-nucleoside inhibitor, replication, transferase-dna complex, transferase/dna
• Biological source: Human herpesvirus 1 (HHV-1, Human herpes simplex virus 1); More
• Total number of polymer chains: 6
• Total formula weight: 290891.60

Authors

Hayes, R.P.,Klein, D. (deposition date: 2021-02-22, release date: 2021-04-07, Last modification date: 2023-10-18)

Primary citation

Hayes, R.P.,Heo, M.R.,Mason, M.,Reid, J.,Burlein, C.,Armacost, K.A.,Tellers, D.M.,Raheem, I.,Shaw, A.W.,Murray, E.,McKenna, P.M.,Abeywickrema, P.,Sharma, S.,Soisson, S.M.,Klein, D.
Structural understanding of non-nucleoside inhibition in an elongating herpesvirus polymerase.
Nat Commun, 12:3040-3040, 2021

PubMed 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.

PubMed: 34031403
DOI: 10.1038/s41467-021-23312-8

Experimental method

X-RAY DIFFRACTION (3.5 Å)