The recent emergence of a novel coronavirus (SARS-CoV-2) in China has caused significant public health concerns. Recently, ACE2 was reported as an entry receptor for SARS-CoV-2. In this study, we present the crystal structure of the C-terminal domain of SARS-CoV-2 (SARS-CoV-2-CTD) spike (S) protein in complex with human ACE2 (hACE2), which reveals a hACE2-binding mode similar overall to that observed for SARS-CoV. However, atomic details at the binding interface demonstrate that key residue substitutions in SARS-CoV-2-CTD slightly strengthen the interaction and lead to higher affinity for receptor binding than SARS-RBD. Additionally, a panel of murine monoclonal antibodies (mAbs) and polyclonal antibodies (pAbs) against SARS-CoV-S1/receptor-binding domain (RBD) were unable to interact with the SARS-CoV-2 S protein, indicating notable differences in antigenicity between SARS-CoV and SARS-CoV-2. These findings shed light on the viral pathogenesis and provide important structural information regarding development of therapeutic countermeasures against the emerging virus. Display omitted •SARS-CoV-2 interacts with hACE2 via S protein CTD•A 2.5-Å structure of SARS-CoV-2-CTD in complex with hACE2 is resolved•The SARS-CoV-2-CTD displays stronger affinity for hACE2 compared with SARS-RBD•SARS-CoV-2 -CTD is antigenically different from SARS-RBD The crystal structure of the C-terminal domain of the SARS-CoV-2 spike protein in complex with human ACE2 reveals insights into the mechanisms of binding of this virus and its differences from SARS.