Publications by authors named "Eoin N Leen"

The replication of foot-and-mouth disease virus (FMDV) is dependent on the virus-encoded 3C protease (3C(pro)). As in other picornaviruses, 3C(pro) performs most of the proteolytic processing of the polyprotein expressed from the large open reading frame in the RNA genome of the virus. Previous work revealed that the 3C(pro) from serotype A-one of the seven serotypes of FMDV-adopts a trypsin-like fold.

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Translation initiation is a critical early step in the replication cycle of the positive-sense, single-stranded RNA genome of noroviruses, a major cause of gastroenteritis in humans. Norovirus RNA, which has neither a 5´ m7G cap nor an internal ribosome entry site (IRES), adopts an unusual mechanism to initiate protein synthesis that relies on interactions between the VPg protein covalently attached to the 5´-end of the viral RNA and eukaryotic initiation factors (eIFs) in the host cell. For murine norovirus (MNV) we previously showed that VPg binds to the middle fragment of eIF4G (4GM; residues 652-1132).

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Article Synopsis
  • Noroviruses are RNA viruses known for their positive-sense single-stranded structure and encode NS6 protease, which is crucial for processing viral proteins by cleaving a polyprotein at specific sites.
  • The study aimed to recreate crystals of murine norovirus NS6 protease to explore protease-substrate relationships, extending its C-terminus to analyze its interactions with the NS7 protein.
  • The crystallization resulted in several constructs revealing similar structures to mature NS6 but lacking direct protease-substrate interactions, despite improved phasing through data corrections and anisotropic refinements.
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Viruses have evolved a variety of mechanisms to usurp the host cell translation machinery to enable translation of the viral genome in the presence of high levels of cellular mRNAs. Noroviruses, a major cause of gastroenteritis in man, have evolved a mechanism that relies on the interaction of translation initiation factors with the virus-encoded VPg protein covalently linked to the 5' end of the viral RNA. To further characterize this novel mechanism of translation initiation, we have used proteomics to identify the components of the norovirus translation initiation factor complex.

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Article Synopsis
  • The study presents the structures of VPg proteins from feline calicivirus (FCV) and murine norovirus (MNV) using nuclear magnetic resonance spectroscopy, highlighting their compact helical arrangements with flexible ends.
  • The FCV VPg features a well-defined three-helix bundle, while the MNV VPg only has the first two helices; both are stabilized by hydrophobic and salt bridge interactions.
  • Despite the structural constraints that suggest difficulties in binding to the viral polymerase for nucleotidylation, mutations in the VPg core impacted its ability to be modified and the virus's infectivity, indicating that further research is needed to understand VPg's role in viral replication.
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Murine noroviruses have emerged as a valuable tool for investigating the molecular basis of infection and pathogenesis of the closely related human noroviruses, which are the major cause of non-bacterial gastroenteritis. The replication of noroviruses relies on the proteolytic processing of a large polyprotein precursor into six non-structural proteins (NS1-2, NS3, NS4, NS5, NS6(pro), NS7(pol)) by the virally-encoded NS6 protease. We report here the crystal structure of MNV NS6(pro), which has been determined to a resolution of 1.

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