Scientists from three national laboratories who specialize in revealing the atomic structure of proteins collaborated to model the complex protein responsible for SARS-CoV-2 replication, revealing potential weak spots for drug development.
The protein-based machine responsible for RNA replication and translation in coronaviruses – and many other viruses – is called the RNA transcription complex (RTC). Multitasking protein machines like the RTC are flexible and have associated molecules, called nonstructural and accessory proteins (Nsps), that exist in a multitude of rapidly rearranging forms depending on the task at hand. Each of these Nsp arrangements expose different parts of the overall RTC surface, which can be examined to find places where potential drug molecules could bind and inhibit the entire machine.
Greg Hura, who heads the Structural Biology Department in the Molecular Biophysics and Integrated Bioimaging (MBIB) Division, co-led the study with Andrzej Joachimiak of Argonne National Laboratory and Hugh M. O’Neill of Oak Ridge National Laboratory. The trio pooled their knowledge and national lab resources to document the structure of as many RTC arrangements as possible, and identify how these forms interact with other viral and human molecules. They combined small-angle X-ray scattering (SAXS), X-ray crystallography, and small-angle neutron scattering (SANS) performed at Berkeley Lab’s Advanced Light Source, Argonne’s Advanced Photon Source, and Oak Ridge’s High Flux Isotope Reactor and Spallation Neutron Source, respectively, on samples of biosynthetically produced RTC.
Of the many structural findings that will help with drug design, one notable discovery is that assembly of the RTC subunits is incredibly precise; the Nsps must follow a specific order of operations to move into place. They also identified how one Nsp specifically recognizes the RNA molecules it acts upon, and how it cuts long strands of copied RNA into their correct lengths. Due to the similarity of RTC proteins across viral strains, the team believe that any drugs developed to block RTC activity could work for multiple viral infections in addition to all COVID-19 variants.
Read more in the Berkeley Lab News Center.