MERS-CoV remains a significant public health threat despite its discovery more than a decade ago. The study provides molecular insights into the interaction between the virus and the host CD26 receptor in order to gain a better understanding of the infection mechanism.
We identify novel interface regions and interacting amino acids, and by that expand the current understanding of the complex's structure. We show how an amino acid substitution, E513A, disrupts the stability of the virus-receptor complex and triggers an allosteric mechanism that affects other residues.
MERS-CoV's zoonotic nature prompts an epidemiological assessment of its transmission from animals to humans. We evaluate the likelihood of potential inter-species transmission of MERS-CoV, specifically from domestic animals to humans.
The Middle East respiratory syndrome (MERS) is a severe respiratory disease with high fatality rates, caused by the Middle East respiratory syndrome coronavirus (MERS-CoV). The virus initiates infection by binding to the CD26 receptor (also known as dipeptidyl peptidase 4 or DPP4) via its spike protein. Although the receptor-binding domain (RBD) of the viral spike protein and the complex between RBD and the extracellular domain of CD26 have been studied using X-ray crystallography, conflicting studies exist regarding the importance of certain amino acids outside the resolved RBD-CD26 complex interaction interface. To gain atomic-level knowledge of the RBD-CD26 complex, we employed computational simulations to study the complex's dynamic behavior as it evolves from its crystal structure to a conformation stable in solution. Our study revealed previously unidentified interaction regions and interacting amino acids within the complex, determined a novel comprehensive RBD-binding domain of CD26, and by that expanded the current understanding of its structure. Additionally, we examined the impact of a single amino acid substitution, E513A, on the complex's stability. We discovered that this substitution disrupts the complex through an allosteric domino-like mechanism that affects other residues. Since MERS-CoV is a zoonotic virus, we evaluated its potential risk of human infection via animals, and suggest a low likelihood for possible infection by cats or dogs. The molecular structural information gleaned from our insights into the RBD-CD26 complex pre-dissociative states may be proved useful not only from a mechanistic view but also in assessing inter-species transmission and in developing anti-MERS-CoV antiviral therapeutics.