Abstract
Icosahedral viral capsids must undergo conformational rearrangements to coordinate essential processes during the viral life cycle. Capturing such conformational flexibility has been technically challenging yet could be key for developing rational therapeutic agents to combat infections. Noroviruses are nonenveloped, icosahedral viruses of global importance to human health. They are a common cause of acute gastroenteritis, yet no vaccines or specific antiviral agents are available. Here, we use genetics and cryo-electron microscopy (cryo-EM) to study the high-resolution solution structures of murine norovirus as a model for human viruses. By comparing our 3 structures (at 2.9- to 3.1-Å resolution), we show that whilst there is little change to the shell domain of the capsid, the radiating protruding domains are flexible, adopting distinct states both independently and synchronously. In doing so, the capsids sample a range of conformational space, with implications for maintaining virion stability and infectivity.
Highlights
High-resolution structural information has been key in improving our understanding of viral life cycles
We used cryo-electron microscopy to determine the structure of wild-type MNV (wtMNV) at 3.1-Å resolution (Fig 1A and S1 Fig). wtMNV was cultivated in RAW264.7 cells, purified by ultracentrifugation through a sucrose cushion and 2 sucrose gradients before being applied to lacey carbon grids and vitrified
We investigated capsid stability by performing Particle Stability Thermal Release (PaSTRy) assays, which employ 2 fluorescent dyes, SYTO-9 and SYPRO-Orange, to assess the stability of viral capsids independently of viral infectivity [21] (Fig 2B)
Summary
High-resolution structural information has been key in improving our understanding of viral life cycles. Viral capsids commonly undergo profound conformational changes during their infection cycles, as well as more subtle dynamics that can be challenging to capture. Understanding such conformational changes can hold the key for the design and development of antiviral agents and vaccines, which are needed for many viral diseases, including those caused by noroviruses. Several clinical trials of virus-like particle (VLP) vaccines have been undertaken, results have been disappointing [2,3].
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