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Structure paper

タイトル	An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike.
ジャーナル・号・ページ	Science, Vol. 370, Issue 6523, Page 1473-1479, Year 2020
掲載日	2020年12月18日
著者	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 要旨	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.
リンク	Science / PubMed:33154106 / PubMed Central
手法	EM (単粒子) / X線回折
解像度	2.05 - 4.18 Å
構造データ	22907 7kkk EMDB-22907: SARS-CoV-2 Spike bound to Nb6 in closed conformation PDB-7kkk: SARS-CoV-2 Spike in complex with neutralizing nanobody Nb6 手法: EM (単粒子) / 解像度: 3.03 Å EMDB-22908: SARS-CoV-2 Spike bound to Nb6 in open conformation 手法: EM (単粒子) / 解像度: 3.8 Å EMDB-22909: SARS-CoV-2 Spike bound to Nb11 in closed conformation 手法: EM (単粒子) / 解像度: 4.18 Å 22910 7kkl EMDB-22910: SARS-CoV-2 Spike bound to mNb6 in closed conformation PDB-7kkl: SARS-CoV-2 Spike in complex with neutralizing nanobody mNb6 手法: EM (単粒子) / 解像度: 2.85 Å EMDB-22911: SARS-CoV-2 Spike bound to Nb11 in open conformation 手法: EM (単粒子) / 解像度: 3.74 Å PDB-7kkj: Structure of anti-SARS-CoV-2 Spike nanobody mNb6 手法: X-RAY DIFFRACTION / 解像度: 2.05 Å
化合物	ChemComp-SO4: SULFATE ION / 硫酸ジアニオン / 硫酸塩 ChemComp-CL: Unknown entry / クロリド / 塩化物 ChemComp-HOH: WATER / 水 ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-アセチル-β-D-グルコサミン / N-アセチルグルコサミン
由来	severe acute respiratory syndrome coronavirus 2 (SARSコロナウイルス2) synthetic construct (人工物)
キーワード	IMMUNE SYSTEM (免疫系) / Complex / Nanobody (ナノボディ) / VHH / VIRAL PROTEIN/IMMUNE SYSTEM (ウイルス性) / VIRAL PROTEIN-IMMUNE SYSTEM complex (ウイルス性)