7e7b
From Proteopedia
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==Cryo-EM structure of the SARS-CoV-2 furin site mutant S-Trimer from a subunit vaccine candidate== | ==Cryo-EM structure of the SARS-CoV-2 furin site mutant S-Trimer from a subunit vaccine candidate== | ||
| - | <StructureSection load='7e7b' size='340' side='right'caption='[[7e7b]]' scene=''> | + | <StructureSection load='7e7b' size='340' side='right'caption='[[7e7b]], [[Resolution|resolution]] 2.60Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7E7B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E7B FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7e7b]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 Severe acute respiratory syndrome coronavirus 2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7E7B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E7B FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7e7b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e7b OCA], [https://pdbe.org/7e7b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e7b RCSB], [https://www.ebi.ac.uk/pdbsum/7e7b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e7b ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ELA:9-OCTADECENOIC+ACID'>ELA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=VCG:2-hydroxyethyl+2-deoxy-3,5-bis-O-(2-hydroxyethyl)-6-O-(2-{[(9E)-octadec-9-enoyl]oxy}ethyl)-alpha-L-xylo-hexofuranoside'>VCG</scene></td></tr> |
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7e7b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e7b OCA], [https://pdbe.org/7e7b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e7b RCSB], [https://www.ebi.ac.uk/pdbsum/7e7b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e7b ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/CO1A1_HUMAN CO1A1_HUMAN] Defects in COL1A1 are the cause of Caffey disease (CAFFD) [MIM:[https://omim.org/entry/114000 114000]; also known as infantile cortical hyperostosis. Caffey disease is characterized by an infantile episode of massive subperiosteal new bone formation that typically involves the diaphyses of the long bones, mandible, and clavicles. The involved bones may also appear inflamed, with painful swelling and systemic fever often accompanying the illness. The bone changes usually begin before 5 months of age and resolve before 2 years of age.<ref>PMID:8988177</ref> <ref>PMID:12660034</ref> <ref>PMID:15864348</ref> Defects in COL1A1 are a cause of Ehlers-Danlos syndrome type 1 (EDS1) [MIM:[https://omim.org/entry/130000 130000]; also known as Ehlers-Danlos syndrome gravis. EDS is a connective tissue disorder characterized by hyperextensible skin, atrophic cutaneous scars due to tissue fragility and joint hyperlaxity. EDS1 is the severe form of classic Ehlers-Danlos syndrome.<ref>PMID:8988177</ref> <ref>PMID:12660034</ref> <ref>PMID:10739762</ref> <ref>PMID:17211858</ref> Defects in COL1A1 are the cause of Ehlers-Danlos syndrome type 7A (EDS7A) [MIM:[https://omim.org/entry/130060 130060]; also known as autosomal dominant Ehlers-Danlos syndrome type VII. EDS is a connective tissue disorder characterized by hyperextensible skin, atrophic cutaneous scars due to tissue fragility and joint hyperlaxity. EDS7A is marked by bilateral congenital hip dislocation, hyperlaxity of the joints, and recurrent partial dislocations.<ref>PMID:8988177</ref> <ref>PMID:12660034</ref> Defects in COL1A1 are a cause of osteogenesis imperfecta type 1 (OI1) [MIM:[https://omim.org/entry/166200 166200]. A dominantly inherited connective tissue disorder characterized by bone fragility and blue sclerae. Osteogenesis imperfecta type 1 is non-deforming with normal height or mild short stature, and no dentinogenesis imperfecta.<ref>PMID:8988177</ref> <ref>PMID:12660034</ref> <ref>PMID:3244312</ref> <ref>PMID:2794057</ref> <ref>PMID:1718984</ref> <ref>PMID:1634225</ref> <ref>PMID:1737847</ref> <ref>PMID:8223589</ref> <ref>PMID:16705691</ref> <ref>PMID:16786509</ref> <ref>PMID:16638323</ref> <ref>PMID:17875077</ref> <ref>PMID:18670065</ref> Defects in COL1A1 are a cause of osteogenesis imperfecta type 2 (OI2) [MIM:[https://omim.org/entry/166210 166210]; also known as osteogenesis imperfecta congenita. A connective tissue disorder characterized by bone fragility, with many perinatal fractures, severe bowing of long bones, undermineralization, and death in the perinatal period due to respiratory insufficiency. Defects in COL1A1 are a cause of osteogenesis imperfecta type 3 (OI3) [MIM:[https://omim.org/entry/259420 259420]. A connective tissue disorder characterized by progressively deforming bones, very short stature, a triangular face, severe scoliosis, grayish sclera, and dentinogenesis imperfecta. Defects in COL1A1 are a cause of osteogenesis imperfecta type 4 (OI4) [MIM:[https://omim.org/entry/166220 166220]; also known as osteogenesis imperfecta with normal sclerae. A connective tissue disorder characterized by moderately short stature, mild to moderate scoliosis, grayish or white sclera and dentinogenesis imperfecta. Genetic variations in COL1A1 are a cause of susceptibility to osteoporosis (OSTEOP) [MIM:[https://omim.org/entry/166710 166710]; also known as involutional or senile osteoporosis or postmenopausal osteoporosis. Osteoporosis is characterized by reduced bone mass, disruption of bone microarchitecture without alteration in the composition of bone. Osteoporotic bones are more at risk of fracture.<ref>PMID:8988177</ref> <ref>PMID:12660034</ref> <ref>PMID:8841196</ref> <ref>PMID:9535665</ref> Note=A chromosomal aberration involving COL1A1 is found in dermatofibrosarcoma protuberans. Translocation t(17;22)(q22;q13) with PDGF.<ref>PMID:8988177</ref> <ref>PMID:12660034</ref> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/CO1A1_HUMAN CO1A1_HUMAN] Type I collagen is a member of group I collagen (fibrillar forming collagen).[https://www.uniprot.org/uniprot/SPIKE_SARS2 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]<ref>PMID:32075877</ref> <ref>PMID:32142651</ref> <ref>PMID:32155444</ref> 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] | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Within a year after its emergence, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 100 million people worldwide with a death toll over 2 million. Vaccination remains the best hope to ultimately put this pandemic to an end. Here, using Trimer-Tag technology, we produced both wild-type (WT) and furin site mutant (MT) S-Trimers for COVID-19 vaccine studies. Cryo-EM structures of the WT and MT S-Trimers, determined at 3.2 A and 2.6 A respectively, revealed that both antigens adopt a tightly closed conformation and their structures are essentially identical to that of the previously solved full-length WT S protein in detergent. The tightly closed conformation is stabilized by fatty acid and polysorbate 80 binding at the receptor binding domains (RBDs) and the N terminal domains (NTDs) respectively. Additionally, we identified an important pH switch in the WT S-Trimer that shows dramatic conformational change and accounts for its increased stability at lower pH. These results validate Trimer-Tag as a platform technology in production of metastable WT S-Trimer as a candidate for COVID-19 subunit vaccine.IMPORTANCEEffective vaccine against SARS-CoV-2 is critical to end the COVID-19 pandemic. Here, using Trimer-Tag technology, we are able to produce stable and large quantities of WT S-Trimer, a subunit vaccine candidate for COVID-19 with high safety and efficacy from animal and Phase 1 clinical trial studies. Cryo-EM structures of the S-Trimer subunit vaccine candidate show that it predominately adopts tightly closed pre-fusion state, and resembles that of the native and full-length spike in detergent, confirming its structural integrity. WT S-Trimer is currently being evaluated in global Phase 2/3 clinical trial. Combining with published structures of the S protein, we also propose a model to dissect the conformation change of the spike protein before receptor binding. | ||
| + | |||
| + | Cryo-EM structure of S-Trimer, a subunit vaccine candidate for COVID-19.,Ma J, Su D, Sun Y, Huang X, Liang Y, Fang L, Ma Y, Li W, Liang P, Zheng S J Virol. 2021 Mar 10. pii: JVI.00194-21. doi: 10.1128/JVI.00194-21. PMID:33692215<ref>PMID:33692215</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7e7b" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| + | [[Category: Severe acute respiratory syndrome coronavirus 2]] | ||
[[Category: Ma J]] | [[Category: Ma J]] | ||
[[Category: Zheng S]] | [[Category: Zheng S]] | ||
Revision as of 08:28, 7 December 2022
Cryo-EM structure of the SARS-CoV-2 furin site mutant S-Trimer from a subunit vaccine candidate
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