A novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) recently emerged and is rapidly spreading in humans, causing COVID-19 1,2 . A key to tackling this pandemic is to understand the receptor recognition mechanism of the virus, which regulates its infectivity, pathogenesis and host range. SARS-CoV-2 and SARS-CoV recognize the same receptor-angiotensin-converting enzyme 2 (ACE2)-in humans 3,4 . Here we determined the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 (engineered to facilitate crystallization) in complex with ACE2. In comparison with the SARS-CoV RBD, an ACE2-binding ridge in SARS-CoV-2 RBD has a more compact conformation; moreover, several residue changes in the SARS-CoV-2 RBD stabilize two virus-binding hotspots at the RBD-ACE2 interface. These structural features of SARS-CoV-2 RBD increase its ACE2-binding affinity. Additionally, we show that RaTG13, a bat coronavirus that is closely related to SARS-CoV-2, also uses human ACE2 as its receptor. The differences among SARS-CoV-2, SARS-CoV and RaTG13 in ACE2 recognition shed light on the potential animal-to-human transmission of SARS-CoV-2. This study provides guidance for intervention strategies that target receptor recognition by SARS-CoV-2.The sudden emergence and rapid spread of SARS-CoV-2 is endangering global health and economy 1,2 . SARS-CoV-2 has caused many more infections, deaths and economic disruptions than SARS-CoV in 2002 . The origin of SARS-CoV-2 remains unclear. Bats are considered the original source of SARS-CoV-2 because a closely related coronavirus, RaTG13, has been isolated from bats 7 . However, the molecular events that led to the possible bat-to-human transmission of SARS-CoV-2 are unknown. Clinically approved vaccines or drugs that specifically target SARS-CoV-2 are also lacking. Receptor recognition by coronaviruses is an important determinant of viral infectivity, pathogenesis and host range 8,9 . It presents a major target for vaccination and antiviral strategies 10 . Here we elucidate the structural and biochemical mechanisms of receptor recognition by SARS-CoV-2.Receptor recognition by SARS-CoV has been extensively studied. A virus-surface spike protein mediates the entry of coronavirus into host cells. The spike protein of SARS-CoV contains a RBD that specifically recognizes ACE2 as its receptor 3,4 . A series of crystal structures of the SARS-CoV RBD from different strains in complex with ACE2 from different hosts has previously been determined 3,11,12 . These structures showed that SARS-CoV RBD contains a core and a receptor-binding motif (RBM); the RBM mediates contacts with ACE2. The surface of ACE2 contains two virus-binding hotspots that are essential for SARS-CoV binding. Several naturally selected mutations in the SARS-CoV RBM surround these hotspots and regulate the infectivity, pathogenesis, and cross-species and human-to-human transmissions of SARS-CoV 3,11,12 .Because of the sequence similarity between the spike proteins of SARS-CoV and SARS-C...

A novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) is causing the global coronavirus disease 2019 (COVID-19) pandemic. Understanding how SARS-CoV-2 enters human cells is a high priority for deciphering its mystery and curbing its spread. A virus surface spike protein mediates SARS-CoV-2 entry into cells. To fulfill its function, SARS-CoV-2 spike binds to its receptor human ACE2 (hACE2) through its receptor-binding domain (RBD) and is proteolytically activated by human proteases. Here we investigated receptor binding and protease activation of SARS-CoV-2 spike using biochemical and pseudovirus entry assays. Our findings have identified key cell entry mechanisms of SARS-CoV-2. First, SARS-CoV-2 RBD has higher hACE2 binding affinity than SARS-CoV RBD, supporting efficient cell entry. Second, paradoxically, the hACE2 binding affinity of the entire SARS-CoV-2 spike is comparable to or lower than that of SARS-CoV spike, suggesting that SARS-CoV-2 RBD, albeit more potent, is less exposed than SARS-CoV RBD. Third, unlike SARS-CoV, cell entry of SARS-CoV-2 is preactivated by proprotein convertase furin, reducing its dependence on target cell proteases for entry. The high hACE2 binding affinity of the RBD, furin preactivation of the spike, and hidden RBD in the spike potentially allow SARS-CoV-2 to maintain efficient cell entry while evading immune surveillance. These features may contribute to the wide spread of the virus. Successful intervention strategies must target both the potency of SARS-CoV-2 and its evasiveness.

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