7b3o

From Proteopedia

Crystal structure of the SARS-CoV-2 RBD in complex with STE90-C11 Fab

Structural highlights

7b3o is a 3 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 2Å
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

The novel betacoronavirus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) causes a form of severe pneumonia disease called coronavirus disease 2019 (COVID-19). To develop human neutralizing anti-SARS-CoV-2 antibodies, antibody gene libraries from convalescent COVID-19 patients were constructed and recombinant antibody fragments (scFv) against the receptor-binding domain (RBD) of the spike protein were selected by phage display. The antibody STE90-C11 shows a subnanometer IC(50) in a plaque-based live SARS-CoV-2 neutralization assay. The in vivo efficacy of the antibody is demonstrated in the Syrian hamster and in the human angiotensin-converting enzyme 2 (hACE2) mice model. The crystal structure of STE90-C11 Fab in complex with SARS-CoV-2-RBD is solved at 2.0 A resolution showing that the antibody binds at the same region as ACE2 to RBD. The binding and inhibition of STE90-C11 is not blocked by many known emerging RBD mutations. STE90-C11-derived human IgG1 with FcgammaR-silenced Fc (COR-101) is undergoing Phase Ib/II clinical trials for the treatment of moderate to severe COVID-19.

A SARS-CoV-2 neutralizing antibody selected from COVID-19 patients binds to the ACE2-RBD interface and is tolerant to most known RBD mutations.,Bertoglio F, Fuhner V, Ruschig M, Heine PA, Abassi L, Klunemann T, Rand U, Meier D, Langreder N, Steinke S, Ballmann R, Schneider KT, Roth KDR, Kuhn P, Riese P, Schackermann D, Korn J, Koch A, Chaudhry MZ, Eschke K, Kim Y, Zock-Emmenthal S, Becker M, Scholz M, Moreira GMSG, Wenzel EV, Russo G, Garritsen HSP, Casu S, Gerstner A, Roth G, Adler J, Trimpert J, Hermann A, Schirrmann T, Dubel S, Frenzel A, Van den Heuvel J, Cicin-Sain L, Schubert M, Hust M Cell Rep. 2021 Jul 27;36(4):109433. doi: 10.1016/j.celrep.2021.109433. Epub 2021 , Jul 7. PMID:34273271^[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
↑ Bertoglio F, Fühner V, Ruschig M, Heine PA, Abassi L, Klünemann T, Rand U, Meier D, Langreder N, Steinke S, Ballmann R, Schneider KT, Roth KDR, Kuhn P, Riese P, Schäckermann D, Korn J, Koch A, Chaudhry MZ, Eschke K, Kim Y, Zock-Emmenthal S, Becker M, Scholz M, Moreira GMSG, Wenzel EV, Russo G, Garritsen HSP, Casu S, Gerstner A, Roth G, Adler J, Trimpert J, Hermann A, Schirrmann T, Dübel S, Frenzel A, Van den Heuvel J, Čičin-Šain L, Schubert M, Hust M. A SARS-CoV-2 neutralizing antibody selected from COVID-19 patients binds to the ACE2-RBD interface and is tolerant to most known RBD mutations. Cell Rep. 2021 Jul 27;36(4):109433. PMID:34273271 doi:10.1016/j.celrep.2021.109433