Molecular basis for receptor recognition and broad host tropism for merbecovirus MjHKU4r-CoV-1

Area of Science:

• Virology
• Structural Biology
• Molecular Mechanisms of Viral Entry

Background:

• A novel pangolin-origin MERS-like coronavirus, MjHKU4r-CoV-1, has been identified.
• This virus is closely related to bat HKU4-CoV and demonstrates infectivity in human organs and transgenic mice.
• MjHKU4r-CoV-1 utilizes the dipeptidyl peptidase 4 (DPP4, also known as CD26) receptor for entry and exhibits broad host tropism.

Purpose of the Study:

• To elucidate the molecular mechanism of MjHKU4r-CoV-1 receptor binding.
• To identify the determinants governing the virus's host range.
• To understand the structural basis of MjHKU4r-CoV-1 interaction with its human receptor.

Main Methods:

• Determined the crystal structure of the MjHKU4r-CoV-1 spike (S) protein receptor-binding domain (RBD) complexed with human CD26 (hCD26).
• Assessed the binding capacity of MjHKU4r-CoV-1 to various animal receptors.
• Performed mutagenesis analyses and homology modeling on CD26 residues.

Main Results:

• The study revealed the structural basis for MjHKU4r-CoV-1 binding to the hCD26 receptor.
• Specific residue sites on CD26 (positions 291, 292, 294, 295, 336, and 344) were identified as critical determinants of MjHKU4r-CoV-1 host range.
• The virus demonstrated broad tropism, interacting with multiple animal receptors.

Conclusions:

• The findings provide a detailed understanding of MjHKU4r-CoV-1's receptor binding mechanism and host tropism.
• Identified key CD26 residues essential for determining the host range of this pangolin coronavirus.
• This research enhances preparedness for potential future outbreaks involving MjHKU4r-CoV-1 or related viruses.