SNAP output for PDB entry 7luf [SNAP web server]

PDB-id

7luf; SNAP-derived features in text and JSON formats; DNAproDB

Class

transferase-DNA

Method

X-ray (3.5 Å)

Summary

Hsv1 polymerase ternary complex with dsDNA and pnu-183792

Reference

Hayes RP, Heo MR, Mason M, Reid J, Burlein C, Armacost KA, Tellers DM, Raheem I, Shaw AW, Murray E, McKenna PM, Abeywickrema P, Sharma S, Soisson SM, Klein D (2021): "Structural understanding of non-nucleoside inhibition in an elongating herpesvirus polymerase." Nat Commun, 12, 3040. doi: 10.1038/s41467-021-23312-8.

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.