Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Affinity maturation endows potent activity onto class 6 SARS-CoV-2 broadly neutralizing antibodies.
Journal, issue, pages	Proc Natl Acad Sci U S A, Vol. 122, Issue 1, Page e2417544121, Year 2025
Publish date	Jan 7, 2025
Authors	Ohan Mazigi / David B Langley / Jake Y Henry / Deborah L Burnett / Meghna Sobti / Gregory J Walker / Romain Rouet / Harikrishnan Balachandran / Helen Lenthall / Jennifer Jackson / Stephanie Ubiparipovic / Peter Schofield / Simon H J Brown / Sebastian R Schulz / Markus Hoffmann / Stefan Pöhlmann / Jeffrey Post / Marianne Martinello / Golo Ahlenstiel / Anthony Kelleher / William D Rawlinson / Stuart G Turville / Rowena A Bull / Alastair G Stewart / Hans-Martin Jäck / Christopher C Goodnow / Daniel Christ /
PubMed Abstract	The emergence of SARS-CoV-2 variants of concern (VOCs) has greatly diminished the neutralizing activity of previously FDA-approved monoclonal antibodies (mAbs), including that of antibody cocktails ...The emergence of SARS-CoV-2 variants of concern (VOCs) has greatly diminished the neutralizing activity of previously FDA-approved monoclonal antibodies (mAbs), including that of antibody cocktails and of first-generation broadly neutralizing antibodies such as S309 (Sotrovimab). In contrast, antibodies targeting cryptic conformational epitopes of the receptor binding domain (RBD) have demonstrated broad activity against emerging variants, but exert only moderate neutralizing activity, which has so far hindered clinical development. Here, we utilize in vitro display technology to identify and affinity-mature antibodies targeting the cryptic class 6 epitope, accessible only in the "up" conformation of the SARS-CoV-2 spike trimer. Increasing antibody affinity into the low picomolar range endowed potent neutralization of VOCs and protection of hACE2 mice from viral challenge. Cryoelectron microscopy and crystal structures of two affinity-matured antibodies (4C12-B12 and 4G1-C2) in complex with RBD highlighted binding modes and epitopes distal from mutational hotspots commonly overserved in VOCs, providing direct structural insights into the observed mutational resistance. Moreover, we further demonstrate that antibodies targeting the class 6 epitope, rather than being an artifact of in vitro selection, are common in the IgG1 memory B cell repertoire of convalescent patients and can be induced in human antibody V-gene transgenic mice through immunization. Our results highlight the importance of very high (picomolar) affinity in the development of neutralizing antibodies and vaccines and suggest an affinity threshold in the provision of broad and long-lasting immunity against SARS-CoV-2.
External links	Proc Natl Acad Sci U S A / PubMed:39746041 / PubMed Central
Methods	EM (single particle) / X-ray diffraction
Resolution	1.873 - 3.18 Å
Structure data	EMDB-46788: VFLIP Spike Trimer with 4C12-B12 Method: EM (single particle) / Resolution: 3.18 Å PDB-8cwi: Fab arm of antibody 10G4 bound to CoV-2 receptor binding domain (RBD) Method: X-RAY DIFFRACTION / Resolution: 1.873 Å PDB-8cwj: Fab arms of antibodies 4C12-B12 and CR3022 bound to pangolin receptor binding domain (pRBD) Method: X-RAY DIFFRACTION / Resolution: 2.449 Å PDB-8cwk: Fab arm of antibodies 4G1-C2 and 10G4 bound to CoV-2 receptor binding domain (RBD) Method: X-RAY DIFFRACTION / Resolution: 2.368 Å
Chemicals	ChemComp-MG: Unknown entry ChemComp-CL: Unknown entry ChemComp-HOH: WATER ChemComp-GOL: GLYCEROL ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose
Source	homo sapiens (human) severe acute respiratory syndrome coronavirus 2 pangolin coronavirus
Keywords	IMMUNE SYSTEM / antibody / CoV-2 / receptor binding domain / class 5 epitope / pangolin