Pathogen-sugar interactions revealed by universal saturation transfer analysis

• DOI: 10.1126/science.abm3125
• Publication Date: 2022-06-23T17:59:10Z
• Authors: Charles J. Buchanan; Ben Gaunt; Peter J. Harrison; Yun Yang; Jiwei Liu; Aziz Khan; Andrew M. Giltrap; Audrey Le Bas; Philip N. Ward; Kapil Gupta; Maud Dumoux; Tiong Kit Tan; Lisa Schimaski; Sergio Daga; Nicola Picchiotti; Margherita Baldas...; Elisa Benetti; Chiara Fallerini; Francesca Fava; Annarita Giliberti; Panagiotis I. Koukos; Matthew J. Davy; Abirami Lakshmina...; Xiaochao Xue; Georgios Papadakis; Lachlan P. Deimel; Virgínia Casablan...; Timothy D. W. Cla...; Alexandre M. J. J...; Quentin J. Sattentau; Simone Furini; Marco Gori; Jiandong Huo; Raymond J. Owens; Christiane Schaff...; Imre Berger; Alessandra Renieri; ; James H. Naismith; Andrew J. Baldwin; Benjamin G. Davis
• Keywords: 0301 basic medicine; /dk/atira/pure/core/keywords/max_planck_bristol_; name=Max Planck Bristol; UNCOVER; Cryoelectron Microscopy; Genetic Variation; Humans; Nuclear Magnetic Resonance, Biomolecular; Polysaccharides; Protein Binding; Protein Domains; COVID-19; Host-Pathogen Interactions; SARS-CoV-2; Sialic Acids; Spike Glycoprotein, Coronavirus; /dk/atira/pure/core/keywords/biodesign_SRI; 03 medical and health sciences; Protein Domains; /dk/atira/pure/core/keywords/max_planck_bristol_; Polysaccharides; Max Planck Bristol; Humans; Nuclear Magnetic Resonance, Biomolecular; /dk/atira/pure/core/keywords/covid_uncover; COVID-19; Cryoelectron Microscopy; Humans; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Sugars; SARS-CoV-2; Bristol BioDesign Institute; Cryoelectron Microscopy; COVID-19; Genetic Variation; Covid19; /dk/atira/pure/core/keywords/covid_uncover; name=UNCOVER; /dk/atira/pure/core/keywords/uob_covid19; /dk/atira/pure/core/keywords/uob_covid19; name=Covid19; Host-Pathogen Interactions; Spike Glycoprotein, Coronavirus; Sialic Acids; /dk/atira/pure/core/keywords/biodesign_SRI; name=Bristol BioDesign Institute; Protein Binding

Many pathogens exploit host cell-surface glycans. However, precise analyses of glycan ligands binding with heavily modified pathogen proteins can be confounded by overlapping sugar signals and/or compounded with known experimental constraints. Universal saturation transfer analysis (uSTA) builds on existing nuclear magnetic resonance spectroscopy to provide an automated workflow for quantitating protein-ligand interactions. uSTA reveals that early-pandemic, B-origin-lineage severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike trimer binds sialoside sugars in an “end-on” manner. uSTA-guided modeling and a high-resolution cryo–electron microscopy structure implicate the spike N-terminal domain (NTD) and confirm end-on binding. This finding rationalizes the effect of NTD mutations that abolish sugar binding in SARS-CoV-2 variants of concern. Together with genetic variance analyses in early pandemic patient cohorts, this binding implicates a sialylated polylactosamine motif found on tetraantennary N-linked glycoproteins deep in the human lung as potentially relevant to virulence and/or zoonosis.