9eh8 | pdb_00009eh8
Structure of the prefusion HKU5-19s Spike trimer (conformation 2)
Structural highlights
FunctionS4WWR5_BCHK5 Spike protein S1: attaches the virion to the cell membrane by interacting with host receptor, initiating the infection.[HAMAP-Rule:MF_04099] Spike protein S2': Acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon virus endocytosis.[HAMAP-Rule:MF_04099] Spike protein S2: mediates fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Under the current model, the protein has at least three conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes.[HAMAP-Rule:MF_04099] Publication Abstract from PubMedDPP4 was considered a canonical receptor for merbecoviruses until the recent discovery of African bat-borne MERS-related coronaviruses using ACE2. The extent and diversity of ACE2 utilization among merbecoviruses and their receptor species tropism remain unknown. Here, we reveal that HKU5 enters host cells utilizing Pipistrellus abramus (P.abr) and several non-bat mammalian ACE2s through a binding mode distinct from that of any other known ACE2-using coronaviruses. We defined the molecular determinants of receptor species tropism and identified a single amino acid mutation enabling HKU5 to utilize human ACE2, providing proof of principle for machine-learning-assisted outbreak preparedness. We show that MERS-CoV and HKU5 have markedly distinct antigenicity and identified several HKU5 inhibitors, including two clinical compounds. Our findings profoundly alter our understanding of coronavirus evolution, as several merbecovirus clades independently evolved ACE2 utilization, and pave the way for developing countermeasures against viruses poised for human emergence. Molecular basis of convergent evolution of ACE2 receptor utilization among HKU5 coronaviruses.,Park YJ, Liu C, Lee J, Brown JT, Ma CB, Liu P, Gen R, Xiong Q, Zepeda SK, Stewart C, Addetia A, Craig CJ, Tortorici MA, Alshukairi AN, Starr TN, Yan H, Veesler D Cell. 2025 Feb 7:S0092-8674(24)01475-2. doi: 10.1016/j.cell.2024.12.032. PMID:39922192[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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