The Crystal Structure of the PB2 Cap-binding Domain of Influenza B Virus Reveals a Novel Cap Recognition Mechanism

Liu, Yong; Yang, Yongfeng; Fan, Jialin; He, Ruina; Luo, Ming; Zheng, Xiaofeng

doi:10.1074/jbc.m115.636464

Cited by 16 publications

(20 citation statements)

References 36 publications

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“…cap , but distinct from the structure in Q325F mutated FluB PB2 cap (16). Conversely, FluB PB2 cap engages GTP by inverting the guanine and ribose moieties 180°around the long axis of the base, similar to the reported structure of FluB PB2 cap ⅐GDP complex.…”

supporting

confidence: 51%

“…This inversion was attributed to the amino acid difference in the FluB Trp-359 position (corresponding to His-357 in FluA), which provides stacking interactions with the guanine moiety (8). However, it is unclear whether this inversion of the ligand is induced by the introduction of the active site mutation, Q325F, which could have significantly altered the ligand binding mode, as evidenced in the drastic changes in binding affinity and specificity after modification of Gln-325 (16 GTP using a conserved binding mode similar to that in FluA PB2…”

mentioning

confidence: 99%

“…Using recombinant viral RNPs, it has been shown that FluA polymerase cleaves RNA capped with m 7 G preferentially, whereas FluB polymerase efficiently cleaves unmethylated GpppG RNA in addition to m 7 G-capped RNA, suggesting that the FluB PB2 contains a more permissive active site and may accommodate a wider range of cap analogs (15). Most recently, a co-structure with m 7 GDP was determined for FluB PB2 containing a Q325F binding site mutation (16). Surprisingly, the guanine and ribose of m 7 GDP in this co-structure invert along the long axis of the base when compared with m 7 GTP bound in FluA PB2.…”

mentioning

confidence: 99%

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

Xie¹,

Wartchow

Shia

et al. 2016

Journal of Biological Chemistry

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supporting

confidence: 51%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Xie¹,

Wartchow

Shia

et al. 2016

Journal of Biological Chemistry

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“…The guanine in GDP bound to influenza B virus PB2cap from B/Jiangxi/BV/2006 (PDB code: 4Q46) [15] is rotated 180° relative to the orientation of the guanine moiety in m 7 GTP bound to influenza A virus PB2cap (Figure 8) [10]. The carbonyl at position 6 of GDP forms hydrogen bonds with the sidechain of Arg322 in 4Q46 instead of Lys376 like in 5EG7.…”

Section: Structural Ccomparisons Between 5eg7 and Pb2cap From B/jiangmentioning

confidence: 99%

“…On the other side of the guanine moiety, Trp357 replaces His357 and participates in stronger π-π stacking interactions [10]. [15] is rotated 180 • relative to the orientation of the guanine moiety in m 7 GTP bound to influenza A virus PB2cap (Figure 8) [10]. The carbonyl at position 6 of GDP forms hydrogen bonds with the sidechain of Arg322 in 4Q46 instead of Lys376 like in 5EG7.…”

Section: Structural Ccomparisons Between 5eg7 and Pb2cap From B/jiangmentioning

confidence: 99%

Characterization of the PB2 Cap Binding Domain Accelerates Inhibitor Design

et al. 2018

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X-ray crystallographic structural determinations of the PB2 cap binding domain (PB2cap) have improved the conformational characterization of the RNA-dependent RNA polymerase machinery (PA, PB2, and PB1) of the influenza virus. Geometrically, the catalytic PB1 subunit resembles the palm of a human hand. PA lies near the thumb region, and PB2 lies near the finger region. PB2 binds the cap moiety in the pre-mRNA of the host cell, while the endonuclease of PA cleaves the pre-mRNA 10-13 nucleotides downstream. The truncated RNA piece performs as a primer for PB1 to synthesize the viral mRNA. Precisely targeting PB2cap with a small molecule inhibitor will halt viral proliferation via interference of the cap-snatching activity. Wild-type and mutant PB2cap from A/California/07/2009 H1N1 were expressed in Escherichia coli, purified by nickel affinity and size exclusion chromatography, crystallized, and subjected to X-ray diffraction experiments. The crystal of mutant PB2cap liganded with m 7 GTP was prepared by co-crystallization. Structures were solved by the molecular replacement method, refined, and deposited in the Protein Data Bank (PDB). Structural determination and comparative analyses of these structures revealed the functions of Glu361, Lys376, His357, Phe404, Phe323, Lys339, His432, Asn429, Gln406, and Met401 in PB2cap, and the dissociation of the influenza A PB2cap C-terminal subdomain (residues 446-479) upon ligand binding. Understanding the role of these residues will aid in the ultimate development of a small-molecule inhibitor that binds both Influenza A and B virus PB2cap.

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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

132

149

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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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The Crystal Structure of the PB2 Cap-binding Domain of Influenza B Virus Reveals a Novel Cap Recognition Mechanism

Cited by 16 publications

References 36 publications

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

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

Characterization of the PB2 Cap Binding Domain Accelerates Inhibitor Design

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

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