Structural understanding of non-nucleoside inhibition in an elongating herpesvirus polymerase

Hayes, Robert P.; Heo, Mee Ra; Mason, Mark; Reid, John; Burlein, Christine; Armacost, Kira A.; Tellers, David M.; Raheem, Izzat; Shaw, Anthony W.; Murray, Edward; McKenna, Philip M.; Abeywickrema, Pravien; Sharma, Sujata; Soisson, Stephen M.; Klein, Daniel

doi:10.1038/s41467-021-23312-8

Structural understanding of non-nucleoside inhibition in an elongating herpesvirus polymerase

Journal Article · Mon May 24 00:00:00 EDT 2021 · Nature Communications

DOI:https://doi.org/10.1038/s41467-021-23312-8· OSTI ID:1787771

^[1]; Heo, Mee Ra ^[1]; Mason, Mark ^[1]; Reid, John ^[1]; Burlein, Christine ^[1]; Armacost, Kira A. ^[1]; Tellers, David M. ^[1]; Raheem, Izzat ^[1]; Shaw, Anthony W. ^[1]; Murray, Edward ^[1]; McKenna, Philip M. ^[1]; Abeywickrema, Pravien ^[1]; Sharma, Sujata ^[1]; ^[1]; Klein, Daniel ^[1]

Merck & Co., Inc., West Point, PA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1787771

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 12; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES
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Structural understanding of non-nucleoside inhibition in an elongating herpesvirus polymerase

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