Ebola virus RNA-directed RNA polymerase (L protein)

The Ebola virus RNA-directed RNA polymerase, known as the L protein, is a multifunctional enzyme essential for the viral life cycle in filoviruses like Ebola virus, a non-segmented negative-sense RNA virus. It catalyzes RNA-dependent RNA polymerization for transcribing viral mRNAs from the ribonucleoprotein (RNP) template, as well as genome replication by synthesizing full-length antigenome and genomic RNAs, with VP35 acting as a critical cofactor that tethers the polymerase to the RNP and supports processivity.[1][2][4] The L protein contains conserved domains including an N-terminal domain (NTD) with a filovirus-specific insertion essential for transcription, a core RdRp domain with motifs A-F forming the fingers-palm-thumb structure, and a GDP polyribonucleotidyltransferase (PRNTase) domain for 5' capping nascent mRNAs.[1] Structural studies reveal conformational dynamics, such as repositioning of the priming loop and supporting helix during initiation-to-elongation switch, and VP35 tetramer interactions stabilizing the complex.[1] In disease, the polymerase drives efficient viral propagation during Ebola infection, making the conserved L-VP35 complex a promising pan-filovirus therapeutic target.[1] Suramin inhibits it by binding the NTP entry channel in the RdRp domain via hydrogen bonds, salt bridges, and hydrophobic interactions with conserved residues like Lys392 and Lys293, blocking substrate access and polymerization.[1] VP30 further regulates transcription initiation at specific promoter elements, balancing transcription and replication.[3] Overall, targeting this polymerase offers potential for broad-spectrum antivirals against hemorrhagic fever-causing filoviruses.[1]

Other names

L proteinlarge proteinEBOV Lfilovirus L polymerase

Non-nucleoside inhibition by blocking NTP entry channel and nascent RNA chain space in RdRp domain