Three-dimensional structure of a mouse-adapted type 2/type 1 poliovirus chimera
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T O Yeates1, D H Jacobson, A Martin
1Department of Molecular Biology, Research Institute of Scripps Clinic, La Jolla, CA 92037.
Abstract:
The crystal structure of V510, a chimeric type 2/type 1 poliovirus, has been determined at 2.6 A resolution. Unlike the parental Mahoney strain of type 1 poliovirus, V510 is able to replicate in the mouse central nervous system, due entirely to the replacement of six amino acids in the exposed BC loop of capsid protein VP1. Significant structural differences between the two strains cluster in a major antigenic site of the virus, located at the apex of the radial projection which surrounds the viral five-fold axis. Residues implicated in the mouse-virulence of poliovirus by genetic studies are located in this area, and include the residues which are responsible for stabilizing the conformation of the BC loop in V510. Despite evidence that this area is not involved in receptor binding in cultured primate cells, the genetic and structural observations suggest that this area plays a critical role in receptor interactions in the mouse central nervous system. These results provide a structural framework for further investigation of the molecular determinants of host and tissue tropism in viruses.
Insights
The crystal structure of a chimeric poliovirus (V510) reveals key VP1 protein changes enabling mouse central nervous system replication. These alterations in a major antigenic site dictate host tropism by influencing receptor interactions.
Area of Science:
- Virology
- Structural Biology
- Molecular Biology
Background:
- Poliovirus host and tissue tropism are critical for pathogenesis.
- Understanding the molecular basis of poliovirus neurovirulence is essential for vaccine development.
Purpose of the Study:
- To determine the crystal structure of the chimeric poliovirus V510.
- To elucidate the structural basis for V510's ability to replicate in the mouse central nervous system.
Main Methods:
- X-ray crystallography at 2.6 A resolution.
- Comparative structural analysis of V510 and the Mahoney strain.
- Genetic analysis of poliovirus virulence factors.
Main Results:
- The crystal structure of V510 was determined, revealing six amino acid substitutions in the VP1 BC loop compared to the Mahoney strain.
- These substitutions cluster in a major antigenic site, stabilizing the BC loop conformation.
- This region, though not involved in primate cell receptor binding, is critical for mouse central nervous system receptor interactions.
Conclusions:
- The structural modifications in V510's VP1 protein are responsible for its mouse neurovirulence.
- The findings provide a structural basis for understanding viral host and tissue tropism.
- This work offers a framework for investigating poliovirus pathogenesis and developing targeted interventions.