9n7e
Eptesicus fuscus ACE2 peptidase domain bound to VsCoV-a7 RBD complex
Structural highlights
Publication Abstract from PubMedDipeptidyl peptidase-4 (DPP4) is a well-established receptor for several MERS-related coronaviruses (MERSr-CoVs) isolated from humans, camels, pangolins, and bats (1-6). However, the receptor usage of many genetically diverse bat MERSr-CoVs with broad geographical distributions remains poorly understood. Recent studies have identified angiotensin-converting enzyme 2 (ACE2) as an entry receptor for multiple merbecovirus clades. Here, using viral antigen and pseudovirus-based functional assays, we demonstrate that several bat merbecoviruses from the HKU25 clade previously thought to utilize DPP4 (7), employ ACE2 as their functional receptor. Cryo-electron microscopy analysis revealed that HsItaly2011 and VsCoV-a7 recognize ACE2 with a binding mode sharing similarity with that of HKU5 but involving remodeled interfaces and distinct ortholog selectivity, suggesting a common evolutionary origin of ACE2 utilization for these two clades of viruses. EjCoV-3, a strain closely related to the DPP4-using MERSr-CoV BtCoV-422, exhibited relatively broad ACE2 ortholog tropism and could utilize human ACE2 albeit suboptimally. Despite differences in entry mechanisms and spike proteolytic activation compared to MERS-CoV, these viruses remain sensitive to several broadly neutralizing antibodies and entry inhibitors. These findings redefine our understanding of the evolution of receptor usage among MERSr-CoVs and highlight the versatility of ACE2 as a functional receptor for diverse coronaviruses. ACE2 utilization of HKU25 clade MERS-related coronaviruses with broad geographic distribution.,Liu C, Park YJ, Ma CB, Stuart C, Gen R, Sun YC, Yang X, Lin MY, Xiong Q, Si JY, Liu P, Veesler D, Yan H bioRxiv [Preprint]. 2025 Feb 19:2025.02.19.639017. doi: , 10.1101/2025.02.19.639017. PMID:40027745[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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