In vivo evolution of human MERS-CoV reveals dynamic remodeling of the DPP4-binding interface originally defined by Lu et al. (Nature, 2013)

The atomic-resolution model of MERS-CoV-DPP4 binding (Lu et al., Nature 2013) provided a crucial framework for understanding coronavirus entry. However, whether this interface remains conserved during human transmission has remained unknown. So building on the landmark structural work of Lu et al., which defined the receptor-binding domain (RBD) of MERS-CoV Spike (residues 367-606) and identified key residues including W535, W553, and V555 as critical for DPP4 engagement, we investigated the conservation of this interface in circulating human strains. Analysis of 272 full-genome human MERS-CoV isolates reveals a striking pattern of in vivo adaptation: while the EMC/2012 lab strain (AFS88936.1) retains the canonical anchor motif, all human-derived sequences exhibit consistent substitutions across the RBD, culminating in a fixed TGA stop codon at Spike position 555 truncating the protein within the receptor-binding motif. This suggests that natural MERS-CoV evolution in human hosts has remodeled the DPP4 interface in ways not captured by the original structural model, which was based on a recombinant RBD from a cell-culture-adapted isolate. Our data underscore the importance of complementing structural biology with large-scale clinical genomic surveillance to capture real-time viral adaptation. All sequences, analysis scripts, and residue-level reports are provided for reproducibility. Refrence: LETTERdoi:10.1038/nature12328Molecular basis of binding between novel humancoronavirus MERS-CoV and its receptor CD26Guangwen Lu1*, Yawei Hu2*, Qihui Wang1*, Jianxun Qi1*, Feng Gao3,4*, Yan Li1, Yanfang Zhang1,5, Wei Zhang1, Yuan Yuan1,6,Jinku Bao4, Buchang Zhang2, Yi Shi7, Jinghua Yan1 & George F. Gao1,5,6,7,8