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Exploring structural dynamics of the MERS-CoV receptor DPP4 and mutant DPP4 receptors

Ahmed L Alaofi1

  • 1Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Journal of Biomolecular Structure & Dynamics
|September 10, 2020
PubMed

Insights

Structural differences in dipeptidyl peptidase 4 (DPP4) receptors explain why mice are not susceptible to MERS-CoV infection, unlike humans. This research used molecular dynamics simulations to reveal key conformational variations.

Area of Science:

  • Structural biology
  • Virology
  • Immunology

Background:

  • Human dipeptidyl peptidase 4 (hDPP4) facilitates MERS-CoV entry, while mouse DPP4 (mDPP4) does not, despite high sequence similarity.
  • Understanding DPP4 receptor variability is crucial for developing MERS-CoV animal models and therapeutics.

Purpose of the Study:

  • To investigate the conformational and structural differences between human and mouse DPP4 receptors.
  • To elucidate the molecular basis for MERS-CoV's differential interaction with hDPP4 and mDPP4.

Main Methods:

  • Molecular dynamics (MD) simulations were employed to analyze DPP4 receptor conformations.
  • Molecular docking techniques were used to study the interaction between MERS-CoV RBD and DPP4 variants.

Main Results:

  • Chimeric mouse DPP4 (cmDPP4) exhibited a compact conformation similar to wild-type hDPP4.
  • A Thr288Ala mutation induced a relaxed conformation and increased flexibility in DPP4 variants.
  • MERS-CoV RBD adopted a "standing" conformation when docked to hDPP4 and cmDPP4.

Conclusions:

  • Conformational differences in DPP4 receptors, particularly around the Thr288 residue, likely explain the differential susceptibility to MERS-CoV.
  • These findings provide insights into MERS-CoV host-pathogen interactions and can inform the development of small animal models.
  • Further structural studies are needed to fully understand the impact of DPP4 conformations on MERS-CoV binding affinity.
Keywords:
DPP4MD simulationsMERS-CoV RBDdockingprotein dynamic

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