Molecular Basis of mRNA Cap Recognition by Influenza B Polymerase PB2 Subunit

Xie, Lili; Wartchow, Charles; Shia, S.; Uehara, Kyoko; Steffek, Micah; Warne, Robert; Sutton, James; Muiru, Gladys T.; Léonard, Vincent H. J.; Bussiere, Dirksen E.; Ma, Xiaolei

doi:10.1074/jbc.m115.693051

Cited by 18 publications

(17 citation statements)

References 29 publications

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“…A and B) between the influenza A and B proteins. In two other crystal structures, that is, the influenza B PB2‐CBD in complex with GTP, and a Q325F mutant form of this protein in complex with m 7 GDP, an inverted conformation for the guanine and ribose moieties was seen. These data indicate structural flexibility of the influenza B PB2‐CBD, which explains its promiscuous cap recognition.…”

Section: Structure and Functions Of The Influenza Virus Polymerase Comentioning

confidence: 90%

“…A similar approach for the influenza B PB2‐CBD (Fig. B) revealed that the binding mode of m 7 GTP is similar in influenza A and B, indicating a conserved methylated cap recognition mechanism. Similar as in other cap‐binding proteins (such as the eukaryotic initiation factor eIF4E) in which the 7‐methylguanine moiety is sandwiched between two aromatic residues, a cation‐π packing interaction occurs between Phe404 and His357 in the influenza A PB2‐CBD, and Phe406 and Trp359 in the influenza B counterpart.…”

Section: Structure and Functions Of The Influenza Virus Polymerase Comentioning

confidence: 99%

“…These data indicate structural flexibility of the influenza B PB2‐CBD, which explains its promiscuous cap recognition. In enzymatic assays with purified vRNPs and binding assays with isolated PB2‐CBD, influenza A displays strict specificity for m 7 G‐capped RNA, while the influenza B protein recognizes various cap structures, including unmethylated GpppG‐RNA.…”

Section: Structure and Functions Of The Influenza Virus Polymerase Comentioning

confidence: 99%

“…Chemical structures of the minimal cap analogue m 7 GTP and reported inhibitors of cap‐binding and X‐ray structures of the PB2‐CBD in complex with the corresponding ligands. (A–D) Comparison of the crystal structures of the PB2‐CBD of influenza A (A; PDB: 2VQZ) or influenza B (B; PDB: 5EFA) PB2‐CBD in complex with m 7 GTP; and influenza A PB2‐CBD with bound compound “11” (C; PDB: 4CB6) or VX‐787 (D; PDB: 4P1U). (E) Cap‐binding inhibitors Cap‐3 and Cap‐7 .…”

Section: Structure and Functions Of The Influenza Virus Polymerase Comentioning

confidence: 99%

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The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

Stevaert

Naesens

2016

Medicinal Research Reviews

138

151

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Influenza viruses cause seasonal epidemics and pandemic outbreaks associated with significant morbidity and mortality, and a huge cost. Since resistance to the existing anti‐influenza drugs is rising, innovative inhibitors with a different mode of action are urgently needed. The influenza polymerase complex is widely recognized as a key drug target, given its critical role in virus replication and high degree of conservation among influenza A (of human or zoonotic origin) and B viruses. We here review the major progress that has been made in recent years in unravelling the structure and functions of this protein complex, enabling structure‐aided drug design toward the core regions of the PA endonuclease, PB1 polymerase, or cap‐binding PB2 subunit. Alternatively, inhibitors may target a protein–protein interaction site, a cellular factor involved in viral RNA synthesis, the viral RNA itself, or the nucleoprotein component of the viral ribonucleoprotein. The latest advances made for these diverse pharmacological targets have yielded agents in advanced (i.e., favipiravir and VX‐787) or early clinical testing, besides several experimental inhibitors in various stages of development, which are all covered here.

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Section: Structure and Functions Of The Influenza Virus Polymerase Comentioning

confidence: 90%

Section: Structure and Functions Of The Influenza Virus Polymerase Comentioning

confidence: 99%

Section: Structure and Functions Of The Influenza Virus Polymerase Comentioning

confidence: 99%

Section: Structure and Functions Of The Influenza Virus Polymerase Comentioning

confidence: 99%

See 2 more Smart Citations

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

Stevaert

Naesens

2016

Medicinal Research Reviews

138

151

View full text Add to dashboard Cite

show abstract

“…The cap-binding domain is also an attractive antiviral target (Figure 3). The X-ray structure of influenza A or B virus PB2 in complex with m7 GTP [49,50] reveals a conserved cap-recognition mechanism in which the methylated guanosine is stacked between two aromatic residues similar to its binding mode with the eukaryotic initiation factor (eIF4E). However, the PB2 folding is unique compared to other cap-binding proteins, raising the possibility to identify specific inhibitors [51].…”

Section: Endonucleases In Cap Snatchingmentioning

confidence: 99%

Biochemical principles and inhibitors to interfere with viral capping pathways

Decroly

Canard

2017

Current Opinion in Virology

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Messenger RNAs are decorated by a cap structure, which is essential for their translation into proteins. Many viruses have developed strategies in order to cap their mRNAs. The cap is either synthetized by a subset of viral or cellular enzymes, or stolen from capped cellular mRNAs by viral endonucleases ('cap-snatching'). Reverse genetic studies provide evidence that inhibition of viral enzymes belonging to the capping pathway leads to inhibition of virus replication. The replication defect results from reduced protein synthesis as well as from detection of incompletely capped RNAs by cellular innate immunity sensors. Thus, it is now admitted that capping enzymes are validated antiviral targets, as their inhibition will support an antiviral response in addition to the attenuation of viral mRNA translation. In this review, we describe the different viral enzymes involved in mRNA capping together with relevant inhibitors, and their biochemical features useful in inhibitor discovery.

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The P(III)‐Amidite Based Synthesis of Stable Isotope Labeled mRNA‐Cap‐Structures Enables their Sensitive Quantitation from Brain Tissue

Ripp,

Krämer,

Barth

et al. 2024

Angewandte Chemie

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The 5’ cap structure is crucial to mRNA function, with its diverse methylation patterns depending on the cellular state. Sensitive analytical methods are sought after to quantify this cap variety also referred to as cap epitranscriptome. To address a bottleneck for accurate and precise quantitation, we report a facile and fast access to high‐quality synthetic standards via a new route, involving P(III)‐amidite chemistry. A range of cap nucleotides and their stable heavy isotopic labeled analogues were derived from nucleoside diphosphates, which themselves were directly prepared in a one‐step reaction sequence starting from unprotected nucleosides using a triphosphorylating reagent in combination with ethylenediamine. Considering a wider scope, the route also enables direct access to magic spot nucleotides and diphosphates of isoprenyl‐alcohols. Stable‐isotope labeled cap nucleotides derived from this route paved the way for the development of a highly sensitive LC‐MS/MS method, applied to the characterization of mouse brain cap epitranscriptomes, which turned out to be very different from those of cultured cell lines of widespread use in the life sciences.

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Molecular Basis of mRNA Cap Recognition by Influenza B Polymerase PB2 Subunit

Cited by 18 publications

References 29 publications

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

Biochemical principles and inhibitors to interfere with viral capping pathways

The P(III)‐Amidite Based Synthesis of Stable Isotope Labeled mRNA‐Cap‐Structures Enables their Sensitive Quantitation from Brain Tissue

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