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Structure paper

タイトル	Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape.
ジャーナル・号・ページ	Science, Vol. 371, Issue 6530, Year 2021
掲載日	2021年2月12日
著者	Paul-Albert Koenig / Hrishikesh Das / Hejun Liu / Beate M Kümmerer / Florian N Gohr / Lea-Marie Jenster / Lisa D J Schiffelers / Yonas M Tesfamariam / Miki Uchima / Jennifer D Wuerth / Karl Gatterdam / Natalia Ruetalo / Maria H Christensen / Caroline I Fandrey / Sabine Normann / Jan M P Tödtmann / Steffen Pritzl / Leo Hanke / Jannik Boos / Meng Yuan / Xueyong Zhu / Jonathan L Schmid-Burgk / Hiroki Kato / Michael Schindler / Ian A Wilson / Matthias Geyer / Kerstin U Ludwig / B Martin Hällberg / Nicholas C Wu / Florian I Schmidt /
PubMed 要旨	The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread, with devastating consequences. For passive immunization efforts, nanobodies have size and cost ...The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread, with devastating consequences. For passive immunization efforts, nanobodies have size and cost advantages over conventional antibodies. In this study, we generated four neutralizing nanobodies that target the receptor binding domain of the SARS-CoV-2 spike protein. We used x-ray crystallography and cryo-electron microscopy to define two distinct binding epitopes. On the basis of these structures, we engineered multivalent nanobodies with more than 100 times the neutralizing activity of monovalent nanobodies. Biparatopic nanobody fusions suppressed the emergence of escape mutants. Several nanobody constructs neutralized through receptor binding competition, whereas other monovalent and biparatopic nanobodies triggered aberrant activation of the spike fusion machinery. These premature conformational changes in the spike protein forestalled productive fusion and rendered the virions noninfectious.
リンク	Science / PubMed:33436526 / PubMed Central
手法	EM (単粒子) / X線回折
解像度	1.87 - 4.01 Å
構造データ	11978 7b14 EMDB-11978, PDB-7b14: Nanobody E bound to Spike-RBD in a localized reconstruction 手法: EM (単粒子) / 解像度: 3.79 Å 11980 7b17 EMDB-11980, PDB-7b17: SARS-CoV-spike RBD bound to two neutralising nanobodies. 手法: EM (単粒子) / 解像度: 4.01 Å 11981 7b18 EMDB-11981, PDB-7b18: SARS-CoV-spike bound to two neutralising nanobodies 手法: EM (単粒子) / 解像度: 2.62 Å 23018 7ksg EMDB-23018, PDB-7ksg: SARS-CoV-2 spike in complex with nanobodies E 手法: EM (単粒子) / 解像度: 3.33 Å PDB-7kn5: Crystal structure of SARS-CoV-2 receptor binding domain complexed with nanobodies VHH E and U 手法: X-RAY DIFFRACTION / 解像度: 1.87 Å PDB-7kn6: Crystal structure of SARS-CoV-2 receptor binding domain complexed with nanobody VHH V and antibody Fab CC12.3 手法: X-RAY DIFFRACTION / 解像度: 2.55 Å PDB-7kn7: Crystal structure of SARS-CoV-2 receptor binding domain complexed with nanobody VHH W and antibody Fab CC12.3 手法: X-RAY DIFFRACTION / 解像度: 2.73 Å
化合物	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-アセチル-β-D-グルコサミン ChemComp-EDO: 1,2-ETHANEDIOL / エチレングリコ-ル ChemComp-HOH: WATER
由来	severe acute respiratory syndrome coronavirus 2 (ウイルス) camelus bactrianus (フタコブラクダ) vicugna pacos (アルパカ) lama glama (ラマ) homo sapiens (ヒト)
キーワード	VIRAL PROTEIN / spike glycoprotein / SARS-CoV-2 / nanobody / VIRAL PROTEIN/IMMUNE SYSTEM / Spike / Coronavirus / COVID-19 / IMMUNE SYSTEM / Nanobody-antigen complex / single-domain antibody / VIRAL PROTEIN-IMMUNE SYSTEM complex / Antibody / spike protein / VIRUS