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Title: Structural basis for therapeutic inhibition of influenza A polymerase PB2 subunit

Journal Article · · Scientific Reports
ORCiD logo [1];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2]
  1. Novartis Inst. for BioMedical Research, Emeryville, CA (United States); DOE/OSTI
  2. Novartis Inst. for BioMedical Research, Emeryville, CA (United States)
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Infuenza virus uses a unique mechanism to initiate viral transcription named cap-snatching. The PB2 subunit of the viral heterotrimeric RNA polymerase binds the cap structure of cellular pre-mRNA to promote its cleavage by the PA subunit. The resulting 11–13 capped oligomer is used by the PB1 polymerase subunit to initiate transcription of viral proteins. VX-787 is an inhibitor of the infuenza A virus pre-mRNA cap-binding protein PB2. This clinical stage compound was shown to bind the minimal cap-binding domain of PB2 to inhibit the cap-snatching machinery. However, the binding of this molecule in the context of an extended form of the PB2 subunit has remained elusive. Here we generated a collection of PB2 truncations to identify a PB2 protein representative of its structure in the viral heterotrimeric protein. We present the crystal structure of VX-787 bound to a PB2 construct that recapitulates VX-787's biological antiviral activity in vitro. This co-structure reveals more extensive interactions than previously identifed and provides insight into the observed resistance profle, afnity, binding kinetics, and conformational rearrangements induced by VX-787.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS); 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:
AC02-05CH11231; AC02-06CH11357
OSTI ID:
1624327
Journal Information:
Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 7; ISSN 2045-2322
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

References (45)

Conformational selection in protein binding and function: Conformational Selection journal September 2014
Influenza virus pleiomorphy characterized by cryoelectron tomography journal December 2006
Crystal structure of the RNA-dependent RNA polymerase from influenza C virus journal October 2015
The Protein Maker: an automated system for high-throughput parallel purification journal August 2011
The role of the priming loop in influenza A virus RNA synthesis journal March 2016
A unique cap(m7GpppXm)-dependent influenza virion endonuclease cleaves capped RNAs to generate the primers that initiate viral RNA transcription journal March 1981
Influenza virus pleiomorphy characterized by cryoelectron tomography journal December 2006
The structural basis for cap binding by influenza virus polymerase subunit PB2 journal May 2008
Conformational selection in protein binding and function: Conformational Selection journal September 2014
Crystal structure of the RNA-dependent RNA polymerase from influenza C virus journal October 2015
Structural insight into cap-snatching and RNA synthesis by influenza polymerase journal November 2014
Structural insight into cap-snatching and RNA synthesis by influenza polymerase journal November 2014
Structure of influenza A polymerase bound to the viral RNA promoter journal November 2014
The Protein Maker: an automated system for high-throughput parallel purification journal August 2011
Structural insights into RNA synthesis by the influenza virus transcription-replication machine journal April 2017
Preclinical Activity of VX-787, a First-in-Class, Orally Bioavailable Inhibitor of the Influenza Virus Polymerase PB2 Subunit journal December 2014
CoESPRIT: A Library-Based Construct Screening Method for Identification and Expression of Soluble Protein Complexes journal February 2011
Transfer of 5'-terminal cap of globin mRNA to influenza viral complementary RNA during transcription in vitro journal April 1979
Emergence and pandemic potential of swine-origin H1N1 influenza virus journal June 2009
Influenza Polymerase Can Adopt an Alternative Configuration Involving a Radical Repacking of PB2 Domains journal January 2016
A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics journal September 2014
The structural basis for cap binding by influenza virus polymerase subunit PB2 journal May 2008
A unique cap(m7GpppXm)-dependent influenza virion endonuclease cleaves capped RNAs to generate the primers that initiate viral RNA transcription journal March 1981
Isosteric replacements of the carboxylic acid of drug candidate VX-787: Effect of charge on antiviral potency and kinase activity of azaindole-based influenza PB2 inhibitors journal May 2015
Structure and nuclear import function of the C-terminal domain of influenza virus polymerase PB2 subunit journal February 2007
A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics journal September 2014
CoESPRIT: A Library-Based Construct Screening Method for Identification and Expression of Soluble Protein Complexes journal February 2011
Genomic RNAs of influenza viruses are held in a circular conformation in virions and in infected cells by a terminal panhandle. journal November 1987
Isosteric replacements of the carboxylic acid of drug candidate VX-787: Effect of charge on antiviral potency and kinase activity of azaindole-based influenza PB2 inhibitors journal May 2015
Discovery of a Novel, First-in-Class, Orally Bioavailable Azaindole Inhibitor (VX-787) of Influenza PB2 journal July 2014
Emergence and pandemic potential of swine-origin H1N1 influenza virus journal June 2009
Essential role of conformational selection in ligand binding journal February 2014
Transfer of 5'-terminal cap of globin mRNA to influenza viral complementary RNA during transcription in vitro journal April 1979
Genomic RNAs of influenza viruses are held in a circular conformation in virions and in infected cells by a terminal panhandle. journal November 1987
Structure of influenza A polymerase bound to the viral RNA promoter journal November 2014
Globin mRNAs are primers for the transcription of influenza viral RNA in vitro journal October 1978
Globin mRNAs are primers for the transcription of influenza viral RNA in vitro journal October 1978
Preclinical Activity of VX-787, a First-in-Class, Orally Bioavailable Inhibitor of the Influenza Virus Polymerase PB2 Subunit journal December 2014
Structure and nuclear import function of the C-terminal domain of influenza virus polymerase PB2 subunit journal February 2007
The role of the priming loop in influenza A virus RNA synthesis journal March 2016
Conformational selection or induced fit: A flux description of reaction mechanism journal July 2009
Conformational selection or induced fit: A flux description of reaction mechanism journal July 2009
Discovery of a Novel, First-in-Class, Orally Bioavailable Azaindole Inhibitor (VX-787) of Influenza PB2 journal July 2014
The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design: THE INFLUENZA VIRUS POLYMERASE COMPLEX journal August 2016
Influenza Polymerase Can Adopt an Alternative Configuration Involving a Radical Repacking of PB2 Domains journal January 2016

Cited By (2)

A Parallel Phenotypic Versus Target-Based Screening Strategy for RNA-Dependent RNA Polymerase Inhibitors of the Influenza A Virus journal September 2019
A Parallel Phenotypic Versus Target-Based Screening Strategy for RNA-Dependent RNA Polymerase Inhibitors of the Influenza A Virus journal September 2019

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