Respiratory syncytial virus large (L) protein (RSV L protein)

The Respiratory syncytial virus large (L) protein, also known as the RSV RNA-directed RNA polymerase or RdRp, is a multifunctional ~250 kDa enzyme that serves as the catalytic core of the viral polymerase complex, responsible for RNA genome replication and transcription into viral mRNAs. It harbors three conserved enzymatic domains: the RNA-dependent RNA polymerase (RdRp) domain for nucleotide polymerization, the polyribonucleotidyl transferase (PRNTase or capping) domain for 5' cap addition, and the methyltransferase (MTase) domain for cap methylation, along with facilitating polyadenylation of subgenomic mRNAs. The L protein forms a complex with the tetrameric phosphoprotein (P), which acts as a cofactor, recruiting other viral proteins like nucleoprotein (N) and M2-1 processivity factor to the helical nucleocapsid template for coordinated RNA synthesis. Cryo-EM structures reveal L in elongation-compatible states bound to P and RNA promoters, with P adopting a tentacular arrangement to grip L and regulate activity. In RSV disease, a major cause of respiratory infection especially in infants, the polymerase is a key therapeutic target, with small-molecule inhibitors like ALS-8112 and MRK-1 blocking replication by mimicking nucleosides or altering the active site. Structures rationalize resistance mechanisms and support antiviral design against this non-segmented negative-sense RNA virus.

Other names

RNA-directed RNA polymeraseRdRpRNA-dependent RNA polymerasereplicasetranscriptase

Nucleoside analog incorporation leading to chain termination, allosteric inhibition of polymerase active site