A broadly neutralizing antibody recognizing a unique epitope with signature motif common across coronaviral families

A broadly neutralizing antibody recognizing a unique epitope with signature motif common across coronaviral families | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A broadly neutralizing antibody recognizing a unique epitope with signature motif common across coronaviral families Guang Yang, Lei Yan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5856104/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Cross-reactive antibodies that bind to diverse epitopes have been identified in Sarbecoviruses, but the precise molecular mechanisms remain poorly understood. This study describes the isolation of a broadly neutralizing monoclonal antibody, 3D1, derived from a fully human combinatorial antibody library that targets the highly conserved HR1 domain of Sarbecoviruses. 3D1 uniquely recognizes a type 1 β-turn fold consisting of a 6-mer epitopic peptide, pepDVVNQN/Q, which forms during a pre-hairpin transition state—a conformation that occurs exclusively before membrane fusion during viral infection. It effectively neutralizes a wide range of live SARS-CoV-2 wild-type strains and variants of concern (VOCs), with the exception of Omicron, which evades neutralization due to a detrimental point mutation (Q954H). Notably, this cryptic epitope reveals a signature binding motif that appears to extend throughout the core region of the glycoprotein of coronaviruses and is also present in various RNA virus orthologs, including those of HIV and Marburgvirus. 3D1 functions as a natural or background antibody capable of binding to a diverse array of non-self antigens. Its cross-reactivity toward a wide variety of antigens underscores the effectiveness of the combinatorial antibody library approach, which encompasses the entire antibody repertoire. Biological sciences/Structural biology/X-ray crystallography Biological sciences/Immunology/Infection Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementarymarterinalsNature.pdf Extended Figure 1-10 and Supplementary table 1-2 Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5856104","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":413244834,"identity":"3c1c00d6-b348-4f0c-9992-cc0bb29a39c7","order_by":0,"name":"Guang Yang","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-7379-6810","institution":"SIAIS，Shanghaitech University","correspondingAuthor":true,"prefix":"","firstName":"Guang","middleName":"","lastName":"Yang","suffix":""},{"id":413244835,"identity":"6ee51e7d-971e-499f-b0e5-0835093def5b","order_by":1,"name":"Lei Yan","email":"","orcid":"https://orcid.org/0000-0003-1775-5533","institution":"SIAIS，Shanghaitech University","correspondingAuthor":false,"prefix":"","firstName":"Lei","middleName":"","lastName":"Yan","suffix":""}],"badges":[],"createdAt":"2025-01-18 16:10:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5856104/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5856104/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":75972788,"identity":"5bbf75e8-d8c5-49ad-9e43-d783d534353f","added_by":"auto","created_at":"2025-02-11 05:58:12","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1847081,"visible":true,"origin":"","legend":"Article File","description":"","filename":"3D1manuscriptNature.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5856104/v1_covered_3f8faaf6-e192-4870-8972-864c72ed05d5.pdf"},{"id":75971787,"identity":"0d9140c7-30ad-4f8a-ade2-0875353b2e7f","added_by":"auto","created_at":"2025-02-11 05:42:09","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1877358,"visible":true,"origin":"","legend":"Extended Figure 1-10 and Supplementary table 1-2","description":"","filename":"SupplementarymarterinalsNature.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5856104/v1/9a54f0f08de7c98c81ad8cda.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"A broadly neutralizing antibody recognizing a unique epitope with signature motif common across coronaviral families","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5856104/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5856104/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Cross-reactive antibodies that bind to diverse epitopes have been identified in Sarbecoviruses, but the precise molecular mechanisms remain poorly understood. 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