National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
AI27193
United States
Massachusetts Consortium on Pathogen Readiness (MassCPR)
SARS-CoV-2 Variants Award
United States
Mercatus Center
Emergent Ventures Fast Grant
United States
Citation
Journal: Sci Immunol / Year: 2022 Title: An antibody from single human V-rearranging mouse neutralizes all SARS-CoV-2 variants through BA.5 by inhibiting membrane fusion. Authors: Sai Luo / Jun Zhang / Alex J B Kreutzberger / Amanda Eaton / Robert J Edwards / Changbin Jing / Hai-Qiang Dai / Gregory D Sempowski / Kenneth Cronin / Robert Parks / Adam Yongxin Ye / ...Authors: Sai Luo / Jun Zhang / Alex J B Kreutzberger / Amanda Eaton / Robert J Edwards / Changbin Jing / Hai-Qiang Dai / Gregory D Sempowski / Kenneth Cronin / Robert Parks / Adam Yongxin Ye / Katayoun Mansouri / Maggie Barr / Novalia Pishesha / Aimee Chapdelaine Williams / Lucas Vieira Francisco / Anand Saminathan / Hanqin Peng / Himanshu Batra / Lorenza Bellusci / Surender Khurana / S Munir Alam / David C Montefiori / Kevin O Saunders / Ming Tian / Hidde Ploegh / Tom Kirchhausen / Bing Chen / Barton F Haynes / Frederick W Alt / Abstract: SARS-CoV-2 Omicron subvariants have generated a worldwide health crisis due to resistance to most approved SARS-CoV-2 neutralizing antibodies and evasion of vaccination-induced antibodies. To manage ...SARS-CoV-2 Omicron subvariants have generated a worldwide health crisis due to resistance to most approved SARS-CoV-2 neutralizing antibodies and evasion of vaccination-induced antibodies. To manage Omicron subvariants and prepare for new ones, additional means of isolating broad and potent humanized SARS-CoV-2 neutralizing antibodies are desirable. Here, we describe a mouse model in which the primary B cell receptor (BCR) repertoire is generated solely through V(D)J recombination of a human V1-2 heavy chain (HC) and, substantially, a human Vκ1-33 light chain (LC). Thus, primary humanized BCR repertoire diversity in these mice derives from immensely diverse HC and LC antigen-contact CDR3 sequences generated by nontemplated junctional modifications during V(D)J recombination. Immunizing this mouse model with SARS-CoV-2 (Wuhan-Hu-1) spike protein immunogens elicited several V1-2/Vκ1-33-based neutralizing antibodies that bound RBD in a different mode from each other and from those of many prior patient-derived V1-2-based neutralizing antibodies. Of these, SP1-77 potently and broadly neutralized all SARS-CoV-2 variants through BA.5. Cryo-EM studies revealed that SP1-77 bound RBD away from the receptor-binding motif via a CDR3-dominated recognition mode. Lattice light-sheet microscopy-based studies showed that SP1-77 did not block ACE2-mediated viral attachment or endocytosis but rather blocked viral-host membrane fusion. The broad and potent SP1-77 neutralization activity and nontraditional mechanism of action suggest that it might have therapeutic potential. Likewise, the SP1-77 binding epitope may inform vaccine strategies. Last, the type of humanized mouse models that we have described may contribute to identifying therapeutic antibodies against future SARS-CoV-2 variants and other pathogens.
Entire : three RBD-down state of SARS-CoV-2 D614G spike in complex with th...
Entire
Name: three RBD-down state of SARS-CoV-2 D614G spike in complex with the SP1-77 neutralizing antibody Fab fragment
Components
Complex: three RBD-down state of SARS-CoV-2 D614G spike in complex with the SP1-77 neutralizing antibody Fab fragment
Complex: Spike glycoprotein
Protein or peptide: Spike glycoprotein
Complex: SP1-77 Fab heavy chain, SP1-77 Fab light chain
Protein or peptide: SP1-77 Fab heavy chain
Protein or peptide: SP1-77 Fab light chain
Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
-
Supramolecule #1: three RBD-down state of SARS-CoV-2 D614G spike in complex with th...
Supramolecule
Name: three RBD-down state of SARS-CoV-2 D614G spike in complex with the SP1-77 neutralizing antibody Fab fragment type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 Details: three RBD-down state of SARS-CoV-2 D614G spike in complex with the SP1-77 neutralizing antibody Fab fragment
In the structure databanks used in Yorodumi, some data are registered as the other names, "COVID-19 virus" and "2019-nCoV". Here are the details of the virus and the list of structure data.
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)
EMDB accession codes are about to change! (news from PDBe EMDB page)
The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
The EM Navigator/Yorodumi systems omit the EMD- prefix.
Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator
Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.
Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi