Structural Analysis of Monomeric RNA-Dependent Polymerases: Evolutionary and Therapeutic Implications

Area of Science:

• Structural biology
• Virology
• Biochemistry

Background:

• Over 20 viral RNA-dependent RNA polymerase and reverse transcriptase crystal structures are available.
• These viral enzymes exhibit a conserved right-hand fold (fingers, palm, thumb) and six key structural motifs.
• A common two-metal-ion polymerization mechanism involving conserved aspartate residues is employed.

Purpose of the Study:

• To compare tertiary structures of polymerases from four main RNA viral groups using new crystal structures.
• To construct a phylogenetic tree including single-stranded negative RNA viral polymerases.
• To develop a general three-dimensional model for the Ebola virus RNA-dependent RNA polymerase.

Main Methods:

• Pairwise comparison of tertiary structures from available crystal structures.
• Homology-based structural prediction approach.
• Phylogenetic analysis incorporating diverse viral polymerases.

Main Results:

• A phylogenetic tree of viral RNA-dependent RNA polymerases was established, including single-stranded negative RNA viruses.
• A general three-dimensional model of the Ebola virus RNA-dependent RNA polymerase was developed.
• The model incorporates conserved motifs and residues crucial for polymerase function.

Conclusions:

• Structural insights into viral RNA-dependent RNA polymerases aid understanding of their function.
• The Ebola virus polymerase model provides a basis for further research.
• Understanding these viral polymerases may explain the efficacy of certain antivirals against Ebola virus infection.