7UPX
Three RBD-down state of SARS-CoV-2 D614G spike in complex with the SP1-77 neutralizing antibody Fab fragment (local refinement of the RBD and Fab variable domains)
Summary for 7UPX
| Entry DOI | 10.2210/pdb7upx/pdb |
| EMDB information | 26677 |
| Descriptor | Spike glycoprotein, SP1-77 Fab heavy chain, SP1-77 Fab light chain, ... (4 entities in total) |
| Functional Keywords | viral protein |
| Biological source | Severe acute respiratory syndrome coronavirus More |
| Total number of polymer chains | 3 |
| Total formula weight | 218388.89 |
| Authors | Zhang, J.,Luo, S.,Kreutzberger, A.,Kirchhausen, T.,Chen, B.,Haynes, B.,Alt, F. (deposition date: 2022-04-18, release date: 2022-08-10, Last modification date: 2024-10-09) |
| Primary citation | Luo, S.,Zhang, J.,Kreutzberger, A.J.B.,Eaton, A.,Edwards, R.J.,Jing, C.,Dai, H.Q.,Sempowski, G.D.,Cronin, K.,Parks, R.,Ye, A.Y.,Mansouri, K.,Barr, M.,Pishesha, N.,Williams, A.C.,Vieira Francisco, L.,Saminathan, A.,Peng, H.,Batra, H.,Bellusci, L.,Khurana, S.,Alam, S.M.,Montefiori, D.C.,Saunders, K.O.,Tian, M.,Ploegh, H.,Kirchhausen, T.,Chen, B.,Haynes, B.F.,Alt, F.W. An antibody from single human V H -rearranging mouse neutralizes all SARS-CoV-2 variants through BA.5 by inhibiting membrane fusion. Sci Immunol, 7:eadd5446-eadd5446, 2022 Cited by PubMed 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 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. PubMed: 35951767DOI: 10.1126/sciimmunol.add5446 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.2 Å) |
Structure validation
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