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Coronaviruses (CoVs) are a broad group of spherical and enveloped viruses that cause diseases in humans and animals. CoVs have become a major threat to public health in the past two decades, exemplified by epidemics of acute respiratory syndromes and, most recently, the coronavirus disease 2019 pandemic. The envelope of CoVs contains spike (S) proteins, which are transmembrane proteins with a crown-like shape involved in cell attachment, cell‒cell fusion, host tropism, and pathogenesis. The receptors for spike proteins in host cells can be glycans and proteins. This review approaches the structural and functional aspects of the S protein of CoVs. Several issues are presented, including the structure‒function relationship, examples of host receptors, S protein-host cell connection, and its role in the entry of the virus into host cells. The S protein is one of the main targets of studies on the evolutionary relationships between CoVs, mapping of cross-host transmission events, changes in virulence, variations in disease severity level, and the development of therapeutic strategies and vaccines.
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