Structure of Machupo virus polymerase in complex with matrix protein Z

Nat Commun. 2021 Oct 25;12(1):6163. doi: 10.1038/s41467-021-26432-3.

Abstract

The Arenaviridae family includes several viruses that cause severe human hemorrhagic fevers with high mortality, with no effective countermeasures currently available. The arenavirus multi-domain L protein is involved in viral transcription and replication and represents a promising target for antiviral drugs. The arenavirus matrix protein Z is a small multi-functional protein that inhibits the activities of the L protein. Here we report the structure of Machupo virus L protein in complex with Z determined by cryo-electron microscopy. The Z protein acts as a staple and binds the L protein with 1:1 stoichiometry at the intersection between the PA-C-like region, RNA-dependent RNA polymerase and PB2-N-like region. Binding of the Z protein may lock the multiple domains of L into a fixed arrangement leading to loss of catalytic activity. These results further our understanding of the inhibitory mechanism of arenavirus replication machinery and provide a novel perspective to develop antiviral drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arenaviruses, New World / chemistry*
  • Arenaviruses, New World / classification
  • Arenaviruses, New World / metabolism
  • Binding Sites
  • Cryoelectron Microscopy
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • RNA-Dependent RNA Polymerase / chemistry*
  • RNA-Dependent RNA Polymerase / metabolism
  • Viral Proteins / chemistry*
  • Viral Proteins / metabolism

Substances

  • Viral Proteins
  • Z protein, Machupo virus
  • RNA-Dependent RNA Polymerase