6yor

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Structure of the SARS-CoV-2 spike S1 protein in complex with CR3022 Fab

Structural highlights

6yor is a 6 chain structure with sequence from 2019-ncov and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:S, 2 (2019-nCoV)
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

There are as yet no licensed therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric spike whose receptor binding domain (RBD) recognizes angiotensin-converting enzyme 2, initiating conformational changes that drive membrane fusion. We find that the monoclonal antibody CR3022 binds the RBD tightly, neutralizing SARS-CoV-2, and report the crystal structure at 2.4 A of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilizing CR3022 epitope is inaccessible in the prefusion spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. Cryogenic electron microscopy (cryo-EM) analysis confirms that incubation of spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope could be useful therapeutically, possibly in synergy with an antibody that blocks receptor attachment.

Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike.,Huo J, Zhao Y, Ren J, Zhou D, Duyvesteyn HME, Ginn HM, Carrique L, Malinauskas T, Ruza RR, Shah PNM, Tan TK, Rijal P, Coombes N, Bewley KR, Tree JA, Radecke J, Paterson NG, Supasa P, Mongkolsapaya J, Screaton GR, Carroll M, Townsend A, Fry EE, Owens RJ, Stuart DI Cell Host Microbe. 2020 Jun 19. pii: S1931-3128(20)30351-6. doi:, 10.1016/j.chom.2020.06.010. PMID:32585135[4]

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

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See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ Huo J, Zhao Y, Ren J, Zhou D, Duyvesteyn HME, Ginn HM, Carrique L, Malinauskas T, Ruza RR, Shah PNM, Tan TK, Rijal P, Coombes N, Bewley KR, Tree JA, Radecke J, Paterson NG, Supasa P, Mongkolsapaya J, Screaton GR, Carroll M, Townsend A, Fry EE, Owens RJ, Stuart DI. Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike. Cell Host Microbe. 2020 Jun 19. pii: S1931-3128(20)30351-6. doi:, 10.1016/j.chom.2020.06.010. PMID:32585135 doi:http://dx.doi.org/10.1016/j.chom.2020.06.010

Contents


PDB ID 6yor

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