Structure, receptor recognition, and antigenicity of the human coronavirus CCoV-HuPn-2018 spike glycoprotein

Tortorici, M. Alejandra; Walls, Alexandra C.; Joshi, Anshu; Park, Young-Jun; Eguia, Rachel; Miranda, Marcos C.; Kepl, Elizabeth; Dosey, Annie; Stevens-Ayers, Terry; Boeckh, Michael; Telenti, Amalio; Lanzavecchia, Antonio; King, Neil P.; Corti, Davide; Bloom, Jesse D; Veesler, David

doi:10.1016/j.cell.2022.05.019

Cited by 46 publications

(47 citation statements)

References 127 publications

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“…Moreover, the Bat37ACE2 N54A mutation (abolishing the N -glycosylation) and NeoCoV W540G/N532G substitutions (eliminating interactions with the glycan) hindered binding. These results confirmed the importance of the protein–glycan interactions identified in viral–receptor recognition, as recently described for the human-infecting CCoV-HuPn-2018 30 . By contrast, the mutation N329A, which abolishes the N -glycosylation at site Asn329, did not have a major effect on receptor function (Fig.…”

Section: The Structural Basis For Ace2 Bindingsupporting

confidence: 89%

Close relatives of MERS-CoV in bats use ACE2 as their functional receptors

Xiong

Cao

et al. 2022

Nature

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114

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Middle East respiratory syndrome coronavirus (MERS-CoV) and several bat coronaviruses use dipeptidyl peptidase-4 (DPP4) as an entry receptor1–4. However, the receptor for NeoCoV—the closest known MERS-CoV relative found in bats—remains unclear5. Here, using a pseudotype virus entry assay, we found that NeoCoV and its close relative, PDF-2180, can efficiently bind to and use specific bat angiotensin-converting enzyme 2 (ACE2) orthologues and, less favourably, human ACE2 as entry receptors through their receptor-binding domains (RBDs) on the spike (S) proteins. Cryo-electron microscopy analysis revealed an RBD–ACE2 binding interface involving protein–glycan interactions, distinct from those of other known ACE2-using coronaviruses. We identified residues 337–342 of human ACE2 as a molecular determinant restricting NeoCoV entry, whereas a NeoCoV S pseudotyped virus containing a T510F RBD mutation efficiently entered cells expressing human ACE2. Although polyclonal SARS-CoV-2 antibodies or MERS-CoV RBD-specific nanobodies did not cross-neutralize NeoCoV or PDF-2180, an ACE2-specific antibody and two broadly neutralizing betacoronavirus antibodies efficiently inhibited these two pseudotyped viruses. We describe MERS-CoV-related viruses that use ACE2 as an entry receptor, underscoring a promiscuity of receptor use and a potential zoonotic threat.

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Section: The Structural Basis For Ace2 Bindingsupporting

confidence: 89%

Close relatives of MERS-CoV in bats use ACE2 as their functional receptors

Xiong

Cao

et al. 2022

Nature

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114

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“…Interestingly, glycan-protein interactions play a crucial role in ACE2 recognition of merbecoviruses, especially the crucial interaction mediated by N54-(or N53 in Rsin and Raeg) glycosylation (determinant A). Similar glycan-protein interaction in receptor engagement has also been reported in other coronaviruses, including SARS-CoV-2 and human-infecting CCoV-HuPn-2018 6,48–50 . It could be interesting to investigate their contribution to host tropism in other coronaviruses.…”

Section: Discussionsupporting

confidence: 71%

Broad host tropism of ACE2-using MERS-related coronaviruses and determinants restricting viral recognition

Xiong

et al. 2022

Preprint

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Phylogenetically distant coronaviruses have evolved to employ ACE2 as their common receptors, including NL63 and many Severe acute respiratory syndrome (SARS) coronavirus-related viruses. Recently, we found two Middle East respiratory syndrome coronaviruses (MERS-CoV)-related bat coronaviruses, NeoCoV and PDF-2180, also use Angiotensin-converting enzyme 2(ACE2) but not MERS-CoV receptor dipeptidyl peptidase 4 (DPP4) for entry. Receptor binding domain (RBD)-binding and pseudovirus entry assays based on a wide range of bat ACE2 orthologs revealed that the two viruses strongly prefer ACE2 from Yangochiropteran bats as compared with Yinpterochiropteran bats, which is not observed in NL63 and SARS-CoV-2. Genetic and structural analyses of the virus-receptor interactions of 50 bat ACE2 orthologs pointed to four crucial host range determinants in two viral binding loops on ACE2. Subsequent functional verifications via mutagenesis on representative ACE2 orthologs confirmed the importance of these determinants on human and bat cells. Remarkably, NeoCoV-T510F, a mutation previously shown to acquire human ACE2 recognition, displayed an expanded potential host range covering most tested bat ACE2, probably due to its reinforced interaction with an evolutionary conserved hydrophobic pocket. Our results elucidated the molecular mechanisms for the species-specific ACE2 usage of MERS-related viruses, offering basic information for assessing the zoonotic risk of these ACE2 utilizing merbecoviruses.

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“…The Orthocoronavirinae subfamily of coronaviruses comprises four genera: Alphacoronavirus , Betacoronavirus , Gammacoronavirus , and Deltacoronavirus . Alphacoronaviruses NL63 and 229E and betacoronaviruses OC43, HKU1, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV, and Middle East respiratory syndrome (MERS)-CoV account for almost all human coronavirus (hCoV) infections, with sporadic infections attributed to canine alphacoronavirus CCoV-HuPn-2018 and porcine deltacoronavirus (PDCoV) ( 1 – 3 ). The spike (S) glycoprotein, which binds to various host receptors for viral entry (table S1), is composed of the S 1 and S 2 subunits, is highly divergent, with only ~30% sequence identity between alpha- and betacoronaviruses, and is the main target of neutralizing antibodies ( 4 – 7 ).…”

mentioning

confidence: 99%

“…and porcine deltacoronavirus (PDCoV) (1)(2)(3). The spike (S) glycoprotein, which binds to various host receptors for viral entry (table S1), is composed of the S 1 and S 2 subunits, is highly divergent, with only ~30% sequence identity between alpha-and betacoronaviruses, and is the main target of neutralizing antibodies (4)(5)(6)(7).…”

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confidence: 99%

ACE2-binding exposes the SARS-CoV-2 fusion peptide to broadly neutralizing coronavirus antibodies

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Jerak

Tortorici

et al. 2022

Science

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The coronavirus spike (S) glycoprotein attaches to host receptors and mediates viral fusion. Using a broad screening approach, we isolated from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune donors seven monoclonal antibodies (mAbs) that bind to all human-infecting coronavirus S proteins. This class of mAbs recognize the fusion peptide and acquire affinity and breadth through somatic mutations. Despite targeting a conserved motif, only some mAbs show broad neutralizing activity in vitro against alpha- and beta-coronaviruses, including animal coronavirus WIV-1 and PDF-2180. Two selected mAbs also neutralize Omicron BA.1 and BA.2 authentic viruses and reduce viral burden and pathology in vivo. Structural and functional analyses show that the fusion peptide-specific mAbs bind with different modalities to a cryptic epitope, which is hidden in prefusion stabilized S, and becomes exposed upon binding of angiotensin-converting enzyme 2 (ACE2) or ACE2-mimicking mAbs.

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Structure, receptor recognition, and antigenicity of the human coronavirus CCoV-HuPn-2018 spike glycoprotein

Cited by 46 publications

References 127 publications

Close relatives of MERS-CoV in bats use ACE2 as their functional receptors

Close relatives of MERS-CoV in bats use ACE2 as their functional receptors

Broad host tropism of ACE2-using MERS-related coronaviruses and determinants restricting viral recognition

ACE2-binding exposes the SARS-CoV-2 fusion peptide to broadly neutralizing coronavirus antibodies

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