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25 Recently a novel coronavirus (2019-nCoV) has emerged from Wuhan, China, 26 causing symptoms in humans similar to those caused by SARS coronavirus (SARS-27 CoV). Since SARS-CoV outbreak in 2002, extensive structural analyses have revealed 28 key atomic-level interactions between SARS-CoV spike protein receptor-binding domain 29 (RBD) and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate 30 both the cross-species and human-to-human transmissions of SARS-CoV. Here we 31 analyzed the potential receptor usage by 2019-nCoV, based on the rich knowledge about 32 SARS-CoV and the newly released sequence of 2019-nCoV. First, the sequence of 2019-33 nCoV RBD, including its receptor-binding motif (RBM) that directly contacts ACE2, is 34 similar to that of SARS-CoV, strongly suggesting that 2019-nCoV uses ACE2 as its 35 receptor. Second, several critical residues in 2019-nCoV RBM (particularly Gln493) 36 provide favorable interactions with human ACE2, consistent with 2019-nCoV's capacity 37 for human cell infection. Third, several other critical residues in 2019-nCoV RBM 38 (particularly Asn501) are compatible with, but not ideal for, binding human ACE2, 39 suggesting that 2019-nCoV has acquired some capacity for human-to-human 40 transmission. Last, while phylogenetic analysis indicates a bat origin of 2019-nCoV, 41 2019-nCoV also potentially recognizes ACE2 from a diversity of animal species (except 42 mice and rats), implicating these animal species as possible intermediate hosts or animal 43 models for 2019-nCoV infections. These analyses provide insights into the receptor 44 usage, cell entry, host cell infectivity and animal origin of 2019-nCoV, and may help 45 epidemic surveillance and preventive measures against 2019-nCoV. 46 47 on March 16, 2020 by guest http://jvi.asm.org/ Downloaded from Significance 48 The recent emergence of Wuhan coronavirus (2019-nCoV) puts the world on 49 alert. 2019-nCoV is reminiscent of the SARS-CoV outbreak in 2002-2003. Our decade-50 long structural studies on the receptor recognition by SARS-CoV have identified key 51 interactions between SARS-CoV spike protein and its host receptor angiotensin-52 converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-53 human transmissions of SARS-CoV. One of the goals of SARS-CoV research was to 54 build an atomic-level iterative framework of virus-receptor interactions to facilitate 55 epidemic surveillance, predict species-specific receptor usage, and identify potential 56 animal hosts and animal models of viruses. Based on the sequence of 2019-nCoV spike 57 protein, we apply this predictive framework to provide novel insights into the receptor 58 usage and likely host range of 2019-nCoV. This study provides a robust test of this 59 reiterative framework, providing the basic, translational and public health research 60 communities with predictive insights that may help study and battle this novel 2019-61 nCoV. 62 63 on March 16, 2020 by guest

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The coronavirus spike protein is a multifunctional molecular machine that mediates coronavirus entry into host cells. It first binds to a receptor on the host cell surface through its S1 subunit and then fuses viral and host membranes through its S2 subunit. Two domains in S1 from different coronaviruses recognize a variety of host receptors, leading to viral attachment. The spike protein exists in two structurally distinct conformations, prefusion and postfusion. The transition from prefusion to postfusion conformation of the spike protein must be triggered, leading to membrane fusion. This article reviews current knowledge about the structures and functions of coronavirus spike proteins, illustrating how the two S1 domains recognize different receptors and how the spike proteins are regulated to undergo conformational transitions. I further discuss the evolution of these two critical functions of coronavirus spike proteins, receptor recognition and membrane fusion, in the context of the corresponding functions from other viruses and host cells.