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Title | An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike. |
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Journal, issue, pages | Science, Vol. 370, Issue 6523, Page 1473-1479, Year 2020 |
Publish date | Dec 18, 2020 |
Authors | Michael Schoof / Bryan Faust / Reuben A Saunders / Smriti Sangwan / Veronica Rezelj / Nick Hoppe / Morgane Boone / Christian B Billesbølle / Cristina Puchades / Caleigh M Azumaya / Huong T Kratochvil / Marcell Zimanyi / Ishan Deshpande / Jiahao Liang / Sasha Dickinson / Henry C Nguyen / Cynthia M Chio / Gregory E Merz / Michael C Thompson / Devan Diwanji / Kaitlin Schaefer / Aditya A Anand / Niv Dobzinski / Beth Shoshana Zha / Camille R Simoneau / Kristoffer Leon / Kris M White / Un Seng Chio / Meghna Gupta / Mingliang Jin / Fei Li / Yanxin Liu / Kaihua Zhang / David Bulkley / Ming Sun / Amber M Smith / Alexandrea N Rizo / Frank Moss / Axel F Brilot / Sergei Pourmal / Raphael Trenker / Thomas Pospiech / Sayan Gupta / Benjamin Barsi-Rhyne / Vladislav Belyy / Andrew W Barile-Hill / Silke Nock / Yuwei Liu / Nevan J Krogan / Corie Y Ralston / Danielle L Swaney / Adolfo García-Sastre / Melanie Ott / Marco Vignuzzi / / Peter Walter / Aashish Manglik / |
PubMed Abstract | The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin-converting enzyme 2 (ACE2). ...The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin-converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryo-electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains locked into their inaccessible down state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia. |
External links | Science / PubMed:33154106 / PubMed Central |
Methods | EM (single particle) / X-ray diffraction |
Resolution | 2.05 - 4.18 Å |
Structure data | EMDB-22907: SARS-CoV-2 Spike bound to Nb6 in closed conformation EMDB-22908: EMDB-22909: EMDB-22910: SARS-CoV-2 Spike bound to mNb6 in closed conformation EMDB-22911: PDB-7kkj: |
Chemicals | ChemComp-SO4: ChemComp-CL: ChemComp-HOH: ChemComp-NAG: |
Source |
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Keywords | IMMUNE SYSTEM / Complex / Nanobody / VHH / VIRAL PROTEIN/IMMUNE SYSTEM / VIRAL PROTEIN-IMMUNE SYSTEM complex |