Multiple independent acquisitions of ACE2 usage in MERS-related coronaviruses

The angiotensin-converting enzyme 2 (ACE2) receptor is shared by various coronaviruses with distinct receptor-binding domain (RBD) architectures, yet our understanding of these convergent acquisition events remains elusive. Here, we report that two European bat MERS-related coronaviruses (MERSr-CoVs) infecting Pipistrellus nathusii (P.nat), MOW15-22 and PnNL2018B, use ACE2 as their receptor, with narrow ortholog specificity. Cryo-electron microscopy structures of the MOW15-22 RBD-ACE2 complex unveil an unexpected and entirely distinct binding mode, mapping 50[A] away from that of any other known ACE2-using coronaviruses. Functional profiling of ACE2 orthologs from 105 mammalian species led to the identification of host tropism determinants, including an ACE2 N432-glycosylation restricting viral recognition, and the design of a soluble P.nat ACE2 mutant with potent viral neutralizing activity. Our findings reveal convergent acquisition of ACE2 usage for merbecoviruses found in European bats, underscoring the extraordinary diversity of ACE2 recognition modes among coronaviruses and the promiscuity of this receptor. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/560486v2_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1967686org.highwire.dtl.DTLVardef@13f8c8borg.highwire.dtl.DTLVardef@1241e38org.highwire.dtl.DTLVardef@3bfd7a_HPS_FORMAT_FIGEXP M_FIG C_FIG