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Structure of the Respiratory Syncytial Virus Polymerase Complex.
- Source :
-
Cell [Cell] 2019 Sep 19; Vol. 179 (1), pp. 193-204.e14. Date of Electronic Publication: 2019 Sep 05. - Publication Year :
- 2019
-
Abstract
- Numerous interventions are in clinical development for respiratory syncytial virus (RSV) infection, including small molecules that target viral transcription 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 polymerase complex and, with the exception of its oligomerization domain, is thought to be intrinsically disordered. Despite their critical roles in RSV transcription and replication, structures of L and P have remained elusive. Here, we describe the 3.2-Å 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.<br /> (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Subjects :
- Acetates chemistry
Animals
Antiviral Agents chemistry
Antiviral Agents therapeutic use
Catalytic Domain
Cryoelectron Microscopy
Deoxycytidine analogs & derivatives
Deoxycytidine chemistry
Deoxycytidine pharmacology
Deoxycytidine therapeutic use
Hydrogen Bonding
Hydrophobic and Hydrophilic Interactions
Phosphoproteins chemistry
Phosphoproteins metabolism
Protein Conformation, alpha-Helical
Protein Interaction Domains and Motifs
Quinolines chemistry
RNA-Dependent RNA Polymerase antagonists & inhibitors
RNA-Dependent RNA Polymerase chemistry
RNA-Dependent RNA Polymerase metabolism
Respiratory Syncytial Virus Infections drug therapy
Respiratory Syncytial Virus Vaccines chemistry
Sf9 Cells
Spodoptera
Viral Proteins chemistry
Viral Proteins metabolism
Virus Replication drug effects
Phosphoproteins ultrastructure
RNA-Dependent RNA Polymerase ultrastructure
Respiratory Syncytial Virus Infections virology
Respiratory Syncytial Virus, Human enzymology
Viral Proteins ultrastructure
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4172
- Volume :
- 179
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 31495574
- Full Text :
- https://doi.org/10.1016/j.cell.2019.08.014