8fxb

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SARS-CoV-2 XBB.1 spike RBD bound to the human ACE2 ectodomain and the S309 neutralizing antibody Fab fragment

Structural highlights

8fxb is a 4 chain structure with sequence from Homo sapiens and Severe acute respiratory syndrome coronavirus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.1Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ACE2_HUMAN Carboxypeptidase which converts angiotensin I to angiotensin 1-9, a peptide of unknown function, and angiotensin II to angiotensin 1-7, a vasodilator. Also able to hydrolyze apelin-13 and dynorphin-13 with high efficiency. May be an important regulator of heart function. In case of human coronaviruses SARS and HCoV-NL63 infections, serve as functional receptor for the spike glycoprotein of both coronaviruses.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain(1) (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting.

Neutralization, effector function and immune imprinting of Omicron variants.,Addetia A, Piccoli L, Case JB, Park YJ, Beltramello M, Guarino B, Dang H, de Melo GD, Pinto D, Sprouse K, Scheaffer SM, Bassi J, Silacci-Fregni C, Muoio F, Dini M, Vincenzetti L, Acosta R, Johnson D, Subramanian S, Saliba C, Giurdanella M, Lombardo G, Leoni G, Culap K, McAlister C, Rajesh A, Dellota E Jr, Zhou J, Farhat N, Bohan D, Noack J, Chen A, Lempp FA, Quispe J, Kergoat L, Larrous F, Cameroni E, Whitener B, Giannini O, Cippa P, Ceschi A, Ferrari P, Franzetti-Pellanda A, Biggiogero M, Garzoni C, Zappi S, Bernasconi L, Kim MJ, Rosen LE, Schnell G, Czudnochowski N, Benigni F, Franko N, Logue JK, Yoshiyama C, Stewart C, Chu H, Bourhy H, Schmid MA, Purcell LA, Snell G, Lanzavecchia A, Diamond MS, Corti D, Veesler D Nature. 2023 Sep;621(7979):592-601. doi: 10.1038/s41586-023-06487-6. Epub 2023 , Aug 30. PMID:37648855^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000 Sep 1;87(5):E1-9. PMID:10969042
↑ Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000 Oct 27;275(43):33238-43. PMID:10924499 doi:http://dx.doi.org/10.1074/jbc.M002615200
↑ Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003 Nov 27;426(6965):450-4. PMID:14647384 doi:http://dx.doi.org/10.1038/nature02145
↑ Addetia A, Piccoli L, Case JB, Park YJ, Beltramello M, Guarino B, Dang H, de Melo GD, Pinto D, Sprouse K, Scheaffer SM, Bassi J, Silacci-Fregni C, Muoio F, Dini M, Vincenzetti L, Acosta R, Johnson D, Subramanian S, Saliba C, Giurdanella M, Lombardo G, Leoni G, Culap K, McAlister C, Rajesh A, Dellota E Jr, Zhou J, Farhat N, Bohan D, Noack J, Chen A, Lempp FA, Quispe J, Kergoat L, Larrous F, Cameroni E, Whitener B, Giannini O, Cippà P, Ceschi A, Ferrari P, Franzetti-Pellanda A, Biggiogero M, Garzoni C, Zappi S, Bernasconi L, Kim MJ, Rosen LE, Schnell G, Czudnochowski N, Benigni F, Franko N, Logue JK, Yoshiyama C, Stewart C, Chu H, Bourhy H, Schmid MA, Purcell LA, Snell G, Lanzavecchia A, Diamond MS, Corti D, Veesler D. Neutralization, effector function and immune imprinting of Omicron variants. Nature. 2023 Sep;621(7979):592-601. PMID:37648855 doi:10.1038/s41586-023-06487-6