Structural basis for human DPP4 receptor recognition by a pangolin MERS-like coronavirus

Area of Science:

• Virology
• Structural Biology
• Molecular Interactions

Background:

• Middle East respiratory syndrome coronavirus (MERS-CoV) and pangolin MERS-like coronavirus MjHKU4r-CoV-1 utilize dipeptidyl peptidase 4 (DPP4) as their cellular entry receptor.
• MjHKU4r-CoV-1 has demonstrated infectivity in transgenic mice expressing human DPP4.

Purpose of the Study:

• To elucidate the mechanism of MjHKU4r-CoV-1 cell entry by determining the structural basis of its interaction with DPP4.
• To compare the binding affinity and determinants of MjHKU4r-CoV-1 with other MERS-like coronaviruses.

Main Methods:

• Determined crystal structures of the MjHKU4r-CoV-1 receptor binding domain (RBD) complexed with human DPP4 (hDPP4) and Malayan pangolin DPP4 (MjDPP4).
• Performed comparative analysis of RBD-DPP4 binding modes and affinities.
• Utilized residue swapping experiments between MjHKU4r-CoV-1 RBD and Ty-BatCoV-HKU4 RBD to identify critical binding determinants.

Main Results:

• The binding mode of MjHKU4r-CoV-1 RBD to hDPP4 is structurally similar to that of MERS-CoV RBD.
• MjHKU4r-CoV-1 RBD exhibits a higher binding affinity for hDPP4 compared to the bat coronavirus Ty-BatCoV-HKU4.
• Key residues responsible for MjHKU4r-CoV-1's interaction with hDPP4 were identified through residue swapping.

Conclusions:

• MjHKU4r-CoV-1 demonstrates enhanced adaptation to the human DPP4 receptor compared to bat HKU4 coronavirus.
• The findings highlight the potential for MjHKU4r-CoV-1 or similar viruses to emerge and infect the human population.
• Structural insights provide a basis for understanding coronavirus-host receptor interactions and predicting zoonotic potential.