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. 2020 Jun 26;23(6):101160.
doi: 10.1016/j.isci.2020.101160. Epub 2020 May 13.

The MERS-CoV Receptor DPP4 as a Candidate Binding Target of the SARS-CoV-2 Spike

Yu Li  1 , Ziding Zhang  1 , Li Yang  2 , Xianyi Lian  1 , Yan Xie  3 , Shen Li  3 , Shuyu Xin  2 , Pengfei Cao  4 , Jianhong Lu  5
Affiliations

The MERS-CoV Receptor DPP4 as a Candidate Binding Target of the SARS-CoV-2 Spike

Yu Li et al. iScience. .

Erratum in

Abstract

The ongoing outbreak of the novel coronavirus pneumonia COVID-19 has caused great number of cases and deaths, but our understanding about the pathogen SARS-CoV-2 remains largely unclear. The attachment of the virus with the cell-surface receptor and a cofactor is the first step for the infection. Here, bioinformatics approaches combining human-virus protein interaction prediction and protein docking based on crystal structures have revealed the high affinity between human dipeptidylpeptidase 4 (DPP4) and the spike (S) receptor-binding domain of SARS-CoV-2. Intriguingly, the crucial binding residues of DPP4 are identical to those that are bound to the MERS-CoV-S. Moreover, E484 insertion and adjacent substitutions should be most essential for this DPP4-binding ability acquirement of SARS-CoV-2-S compared with SARS-CoV-S. This potential utilization of DPP4 as a binding target for SARS-CoV-2 may offer novel insight into the viral pathogenesis and help the surveillance and therapeutics strategy for meeting the challenge of COVID-19.

Keywords: Crystallography; Molecular Structure; Virology.

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Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Figures

None
Graphical abstract
Figure 1
Figure 1
The Analyses in the Binding of the Viral Spike Proteins and DPP4 or ACE2 (A) Free energy for the binding between each of three CoV spike (S) proteins and DPP4 or ACE2. Note that all the complexes were downloaded or predicted through ZDOCK based on protein crystal structures. (B) The structure of predicted interaction complex of SARS-CoV-2-S RBD (yellow) and DPP4 (wheat). The detailed binding interface is magnified separately as indicated. (C) The structural model of SARS-CoV-2-S RBD bound with DPP4 is superimposed with the crystal structure of MERS-CoV-S RBD. The contact residues of DPP4 (wheat) bound with either MERS-CoV-S RBD (light blue) or SARS-CoV-2-S RBD (yellow) are displayed in the right two panels.
Figure 2
Figure 2
Comparison of the RBD Structures of Every Two Among Three Viruses RMSD (root-mean-square deviation) value (Å) can be used for the estimation of the structural similarity of every two proteins. The smaller the RMSD, higher the similarity between both structures.
Figure 3
Figure 3
Comparison and Mutation of the Key Residues for the Binding of SARS-CoV-2-S RBD and DPP4 (A) Sequence comparison of the key residues between SARS-CoV-2-S and SARS-CoV-S RBDs. There are an insertion and adjacent substitutions at E484, and a Q498Y substitution in SARS-CoV-2-S RBD. (B) Effect of mutation at the key residues on the binding free energy. Virtual mutations of single key residues could impact the free energy, especially for D405A and E484A. WT, wild-type. (C) Comparison of the key residues between human and pangolin DPP4 protein sequences. Both shared the completely identical key residues including K267, L294, I295, R317, R336, and Q344.
See this image and copyright information in PMC

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