Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein
| العنوان: | Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein |
|---|---|
| المؤلفون: | Christine Toelzer, Imre Berger, Frederic Garzoni, Maia Kavanagh Williamson, Julien Capin, Oskar Staufer, Joachim P. Spatz, Andrew D. Davidson, Kapil Gupta, Deborah K. Shoemark, Daniel J. Fitzgerald, Adrian J. Mulholland, Rachel Milligan, Ufuk Borucu, Christiane Schaffitzel, K.N. Sathish Yadav |
| المصدر: | Science Toelzer, C, Gupta, K, Yadav, S K N, Borucu, U, Davidson, A D, Kavanagh Williamson, M, Shoemark, D K, Garzoni, F, Staufer, O, Milligan, R, Capin, J, Mulholland, A J, Berger, I & Schaffitzel, C 2020, ' Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein ', Science, vol. 370, no. 6517, eabd3255 . https://doi.org/10.1126/science.abd3255Test Science (New York, N.y.) |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Models, Molecular, Linoleic acid, viruses, UNCOVER, BrisSynBio, Peptidyl-Dipeptidase A, Linoleic Acid, Betacoronavirus, chemistry.chemical_compound, Protein structure, Report, Fatty acid binding, Max Planck Bristol, Chlorocebus aethiops, Animals, Humans, Protein Interaction Domains and Motifs, Amino Acid Sequence, Binding site, skin and connective tissue diseases, Vero Cells, Peptide sequence, chemistry.chemical_classification, Binding Sites, Multidisciplinary, SARS-CoV-2, Cryoelectron Microscopy, Bristol BioDesign Institute, Biochem, Fatty acid, virus diseases, Covid19, Protein Structure, Tertiary, Cell biology, respiratory tract diseases, body regions, Severe acute respiratory syndrome-related coronavirus, chemistry, Spike Glycoprotein, Coronavirus, Middle East Respiratory Syndrome Coronavirus, Tissue tropism, Angiotensin-Converting Enzyme 2, Glycoprotein, Reports |
| الوصف: | Locking down the SARS-CoV-2 spike Many efforts to develop therapies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are focused on the spike (S) protein trimer that binds to the host receptor. Structures of trimeric S protein show its receptor-binding domain in either an up or a down conformation. Toelzer et al. produced SARS-CoV-2 S in insect cells and determined the structure by cryo–electron microscopy. In their dataset, the closed form was predominant and was stabilized by binding linoleic acid, an essential fatty acid. A similar binding pocket appears to be present in previous highly pathogenic coronaviruses, and past studies suggested links between viral infection and fatty acid metabolism. The pocket could be exploited to develop inhibitors that trap S protein in the closed conformation. Science, this issue p. 725 The SARS-CoV-2 spike binds linoleic acid, a key molecule in inflammation, immune modulation, and membrane fluidity. Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents a global crisis. Key to SARS-CoV-2 therapeutic development is unraveling the mechanisms that drive high infectivity, broad tissue tropism, and severe pathology. Our 2.85-angstrom cryo–electron microscopy structure of SARS-CoV-2 spike (S) glycoprotein reveals that the receptor binding domains tightly bind the essential free fatty acid linoleic acid (LA) in three composite binding pockets. A similar pocket also appears to be present in the highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). LA binding stabilizes a locked S conformation, resulting in reduced angiotensin-converting enzyme 2 (ACE2) interaction in vitro. In human cells, LA supplementation synergizes with the COVID-19 drug remdesivir, suppressing SARS-CoV-2 replication. Our structure directly links LA and S, setting the stage for intervention strategies that target LA binding by SARS-CoV-2. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::900a1a0a17e2248e7197013081ee0f35Test https://pubmed.ncbi.nlm.nih.gov/32958580Test/ |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....900a1a0a17e2248e7197013081ee0f35 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |