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Published on: December 21, 2019
Analysis of flavivirus NS5 methyltransferase cap binding
Brian J Geiss1, Aaron A Thompson, Andrew J Andrews
1Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, USA. Brian.Geiss@colostate.edu
Journal of Molecular Biology
|December 23, 2008
Summary
Flavivirus RNA methyltransferase (MTase) enzymes bind viral RNA caps through conserved structural interactions. Key binding points involve the guanine ring and alpha-phosphate, ensuring specific recognition for viral RNA capping.
Area of Science:
- Structural biology
- Virology
- Biochemistry
Background:
- Flavivirus 2'-O-nucleoside N-terminal RNA methyltransferase (MTase) enzymes are crucial for viral RNA cap methylation.
- Understanding the mechanism of viral RNA cap binding is essential for developing antiviral strategies.
Purpose of the Study:
- To elucidate the structural and biochemical mechanisms of guanosine cap binding by dengue (DEN) and yellow fever (YF) virus MTase enzymes.
- To characterize the protein-cap interactions and guanine specificity.
Main Methods:
- High-resolution crystal structure determination of DEN2 MTase and YF virus MTase domain (apo and complexed with GTP analog).
- Biochemical characterization using guanosine triphosphate analog competition assays and mutagenesis analysis.
Main Results:
- Detailed structures reveal conserved DEN and YF MTase domains, highlighting structural conservation across flaviviruses.
- Identified key interaction points: guanine ring (pi-pi stacking, water bridge, hydrogen bonds), ribose 2' hydroxyl, and alpha-phosphate.
- Guanine ring and alpha-phosphate interactions contribute significantly to binding energy; specific recognition is mediated by hydrogen bonds and a water bridge.
Conclusions:
- Flavivirus MTases exhibit high structural conservation in cap binding.
- A detailed model for flavivirus MTase-RNA cap binding is presented, emphasizing specific guanine recognition and strong binding energy contributions.
