an important determinant of species specificity, tissue tropism, virulence, and pathogenesis. Pathogenesis depends upon the ability of a virus to dock and enter into a suitable human host cell. For example, the highly pathogenic emerging group 2 coronavirus that causes severe acute respiratory syndrome, coronavirus (SARS-CoV) and a distantly related less pathogenic group 1 human coronavirus, NL63-CoV, both encode a large 180/90kDa spike glycoprotein (S) that engages a host cellular receptor(s) to mediate docking and entry into cells. The SARS-CoV and NL63-CoV S glycoproteins are about 40 percent identical and encode novel, yet unrelated receptor binding domains (RBD) in S that engage the same cellular receptor, angiotensin-converting enzyme 2 (ACE2) to mediate virus docking and entry into cells. Despite the absence of structural homology in the RBD cores of NL63-CoV and SARS-CoV, the two viruses recognize common ACE2 regions by using novel protein-protein folds and interaction networks. On the basis of sequence, it was not possible to predict that the two highly divergent coronavirus RBDs would engage a similar “hot spot” on the surface of the ACE2 receptor and thus mediate docking and entry into cells. Moreover, the pathogenic potential of the two human coronaviruses are distinct: SARS-CoV causes an atypical pneumonia that results in acute respiratory distress syndrome with mortality exceeding 50 percent in people over 60 years old, whereas NL63-CoV causes a self-limiting denuding bronchiolitis and croup, primarily in infants and children. Clearly, other factors besides virus-receptor interaction and entry are regulating severe acute end-stage lung-disease outcomes during SARS-CoV infection, and this complicates sequence-based predictions of virus-receptor interaction networks and virulence outcomes (Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19970-19974. Epub 2009 Nov 9. Crystal structure of NL63 respiratory coronavirus receptor-binding domain complexed with its human receptor (Wu, Li et al. 2009).