Abstract
ACE2 has been established as the main receptor for SARS-CoV-2. Since other human coronaviruses are known to use co-receptors for viral cell entry, it has been suggested that DPP4 (CD26) could be a potential additional binding target or co-receptor, supported by early molecular docking simulation studies. However, recent biophysical studies have shown this interaction to be very weak. We have conducted detailed molecular docking simulations to predict the potential binding interactions between the receptor binding domain (RBD) of the spike protein of SARS-CoV-2 and DPP4 and compare them with the interactions observed in the experimentally determined structure of the complex of MERS-CoV with DPP4. Whilst the overall binding mode of the RBD of SARS-CoV-2 to DPP4 is predicted to be similar to that observed in the MERS-CoV-DPP4 complex, including a number of equivalent interactions, important differences in the amino acid sequences of SARS-CoV-2 and MERS-CoV result in substantially weakened interactions with DPP4. This is shown to arise from differences in the predicted proximity, nature and secondary structure at the binding interface on the RBD of SARS-CoV-2. These findings do not support DPP4 being a significant receptor for SARS-CoV-2.
Highlights
In December 2019, the first cases of a novel coronavirus were reported in Wuhan (China) and since named SARS-CoV-2, which causes the respiratory syndrome COVID-19, characterised by fever, dry cough, breathing difficulties and in severe cases, pneumonia [1]
It has been well-established that SARS-CoV binds to the human angiotensin-converting enzyme 2, whilst MERS-CoV binds to human dipeptidyl peptidase 4 [1,2,3,4,5,6,7]
Experimental studies have established that the spike protein of SARS-CoV-2 can bind to the ACE2 receptor, and various crystal structures have been reported of the receptor binding domain (RBD) of SARS-CoV-2 in complex with ACE2 [2,3,4,8]
Summary
In December 2019, the first cases of a novel coronavirus were reported in Wuhan (China) and since named SARS-CoV-2, which causes the respiratory syndrome COVID-19, characterised by fever, dry cough, breathing difficulties and in severe cases, pneumonia [1]. It is speculated that SARS-CoV-2 is closer to the horseshoe bat coronavirus RaTG13 because it shares over 93% genetic sequence identity, whilst it shares less than 80% sequence identity with SARS-CoV and MERS-CoV [1]. It has been well-established that SARS-CoV binds to the human angiotensin-converting enzyme 2 (hACE2), whilst MERS-CoV binds to human dipeptidyl peptidase 4 (hDPP4 or hCD26) [1,2,3,4,5,6,7]. Most studies agree that SARS-CoV-2 binds more strongly to the ACE2 receptor than SARS-CoV does [8]
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