Structure of the Respiratory Syncytial Virus Polymerase Complex
Abstract
Numerous interventions are in clinical development
for respiratory syncytial virus (RSV) infection,
including small molecules that target viral transcrip-
tion and replication. These processes are catalyzed
by a complex comprising the RNA-dependent RNA
polymerase (L) and the tetrameric phosphoprotein
(P). RSV P recruits multiple proteins to the polymer-
ase complex and, with the exception of its oligomer-
ization domain, is thought to be intrinsically
disordered. Despite their critical roles in RSV tran-
scription and replication, structures of L and P have
remained elusive. Here, we describe the 3.2-A˚ cryo-
EM structure of RSV L bound to tetrameric P. The
structure reveals a striking tentacular arrangement
of P, with each of the four monomers adopting a
distinct conformation. The structure also rationalizes
inhibitor escape mutants and mutations observed in
live-attenuated vaccine candidates. These results
provide a framework for determining the molecular
underpinnings of RSV replication and transcription
and should facilitate the design of effective RSV
inhibitors
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