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SARS-CoV-2 Nsp16 activation mechanism and a cryptic pocket with pan-coronavirus antiviral potential

Neha Vithani1, Michael D Ward1, Maxwell I Zimmerman1

  • 1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri; Center for Science and Engineering of Living Systems, Washington University in St. Louis, St. Louis, Missouri.

Biophysical Journal
|April 1, 2021
PubMed

Insights

Coronaviruses use nonstructural protein 16 (Nsp16) for immune evasion. This study reveals how Nsp10 activates Nsp16 and identifies a potential target for pan-coronavirus antivirals.

Area of Science:

  • Virology
  • Structural Biology
  • Drug Discovery

Background:

  • Coronaviruses, including SARS-CoV-2, pose significant global health threats due to their rapid replication and immune evasion strategies.
  • Nonstructural protein 16 (Nsp16), a 2'-O-methyltransferase, is crucial for coronavirus immune evasion by methylating viral RNA.
  • Nsp16 requires its binding partner, Nsp10, for enzymatic activation, a mechanism not fully understood.

Purpose of the Study:

  • To elucidate the activation mechanism of Nsp16 by its binding partner Nsp10.
  • To identify potential druggable cryptic pockets in Nsp16 for antiviral development.
  • To explore the possibility of developing pan-coronavirus antivirals targeting Nsp16.

Main Methods:

  • Extensive molecular dynamics (MD) simulations (over 1 ms) of Nsp16 and the Nsp16/Nsp10 complex.
  • Application of Markov state models to analyze conformational changes and identify functional states.
  • Structural analysis to detect and characterize cryptic pockets within Nsp16.

Main Results:

  • Nsp10 binding induces significant conformational shifts in Nsp16, activating its methyltransferase activity.
  • A conserved cryptic pocket was identified in SARS-CoV-2 Nsp16, which is also present in SARS-CoV-1 and MERS Nsp16.
  • This cryptic pocket is absent in the human homolog, CMTr1, suggesting Nsp16-specific targeting.

Conclusions:

  • The study provides a detailed mechanism for Nsp10-mediated activation of Nsp16.
  • The identified cryptic pocket represents a promising target for developing novel, broad-spectrum antiviral therapies against coronaviruses.
  • Targeting this pocket could stabilize Nsp16 in its inactive state, inhibiting viral replication.

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