7m6d

From Proteopedia

Structure of the SARS-CoV-2 RBD in complex with neutralizing antibodies BG4-25 and CR3022

Structural highlights

7m6d is a 5 chain structure with sequence from Homo sapiens and Severe acute respiratory syndrome coronavirus 2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.1Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SPIKE_SARS2 attaches the virion to the cell membrane by interacting with host receptor, initiating the infection (By similarity). Binding to human ACE2 receptor and internalization of the virus into the endosomes of the host cell induces conformational changes in the Spike glycoprotein (PubMed:32142651, PubMed:32075877, PubMed:32155444). Uses also human TMPRSS2 for priming in human lung cells which is an essential step for viral entry (PubMed:32142651). Proteolysis by cathepsin CTSL may unmask the fusion peptide of S2 and activate membranes fusion within endosomes.[HAMAP-Rule:MF_04099]^[1] ^[2] ^[3] mediates fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Under the current model, the protein has at least three conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes.[HAMAP-Rule:MF_04099] Acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon virus endocytosis.[HAMAP-Rule:MF_04099]

Publication Abstract from PubMed

Monoclonal antibodies (mAbs) are a focus in vaccine and therapeutic design to counteract severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants. Here, we combined B cell sorting with single-cell VDJ and RNA sequencing (RNA-seq) and mAb structures to characterize B cell responses against SARS-CoV-2. We show that the SARS-CoV-2-specific B cell repertoire consists of transcriptionally distinct B cell populations with cells producing potently neutralizing antibodies (nAbs) localized in two clusters that resemble memory and activated B cells. Cryo-electron microscopy structures of selected nAbs from these two clusters complexed with SARS-CoV-2 spike trimers show recognition of various receptor-binding domain (RBD) epitopes. One of these mAbs, BG10-19, locks the spike trimer in a closed conformation to potently neutralize SARS-CoV-2, the recently arising mutants B.1.1.7 and B.1.351, and SARS-CoV and cross-reacts with heterologous RBDs. Together, our results characterize transcriptional differences among SARS-CoV-2-specific B cells and uncover cross-neutralizing Ab targets that will inform immunogen and therapeutic design against coronaviruses.

B cell genomics behind cross-neutralization of SARS-CoV-2 variants and SARS-CoV.,Scheid JF, Barnes CO, Eraslan B, Hudak A, Keeffe JR, Cosimi LA, Brown EM, Muecksch F, Weisblum Y, Zhang S, Delorey T, Woolley AE, Ghantous F, Park SM, Phillips D, Tusi B, Huey-Tubman KE, Cohen AA, Gnanapragasam PNP, Rzasa K, Hatziioanno T, Durney MA, Gu X, Tada T, Landau NR, West AP Jr, Rozenblatt-Rosen O, Seaman MS, Baden LR, Graham DB, Deguine J, Bieniasz PD, Regev A, Hung D, Bjorkman PJ, Xavier RJ Cell. 2021 Jun 10;184(12):3205-3221.e24. doi: 10.1016/j.cell.2021.04.032. Epub , 2021 Apr 24. PMID:34015271^[4]

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

References

↑ Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, Graham BS, McLellan JS. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020 Feb 19. pii: science.abb2507. doi: 10.1126/science.abb2507. PMID:32075877 doi:http://dx.doi.org/10.1126/science.abb2507
↑ Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C, Pohlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052. Epub 2020, Mar 5. PMID:32142651 doi:http://dx.doi.org/10.1016/j.cell.2020.02.052
↑ Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020 Mar 6. pii: S0092-8674(20)30262-2. doi: 10.1016/j.cell.2020.02.058. PMID:32155444 doi:http://dx.doi.org/10.1016/j.cell.2020.02.058
↑ Scheid JF, Barnes CO, Eraslan B, Hudak A, Keeffe JR, Cosimi LA, Brown EM, Muecksch F, Weisblum Y, Zhang S, Delorey T, Woolley AE, Ghantous F, Park SM, Phillips D, Tusi B, Huey-Tubman KE, Cohen AA, Gnanapragasam PNP, Rzasa K, Hatziioanno T, Durney MA, Gu X, Tada T, Landau NR, West AP Jr, Rozenblatt-Rosen O, Seaman MS, Baden LR, Graham DB, Deguine J, Bieniasz PD, Regev A, Hung D, Bjorkman PJ, Xavier RJ. B cell genomics behind cross-neutralization of SARS-CoV-2 variants and SARS-CoV. Cell. 2021 Jun 10;184(12):3205-3221.e24. PMID:34015271 doi:10.1016/j.cell.2021.04.032