Pathogen-sugar interactions revealed by universal saturation transfer analysis


  • C.J. Buchanan
  • B. Gaunt
  • P.J. Harrison
  • Y. Yang
  • J. Liu
  • A. Khan
  • A.M. Giltrap
  • A. Le Bas
  • P.N. Ward
  • K. Gupta
  • M. Dumoux
  • T.K. Tan
  • L. Schimaski
  • S. Daga
  • N. Picchiotti
  • M. Baldassarri
  • E. Benetti
  • C. Fallerini
  • F. Fava
  • A. Giliberti
  • P.I. Koukos
  • M.J. Davy
  • A. Lakshminarayanan
  • X. Xue
  • G. Papadakis
  • L.P. Deimel
  • V. Casablancas-Antràs
  • T.D.W. Claridge
  • A.M.J.J. Bonvin
  • Q.J. Sattentau
  • S. Furini
  • M. Gori
  • J. Huo
  • R.J. Owens
  • C. Schaffitzel
  • I. Berger
  • A. Renieri
  • J.H. Naismith
  • A.J. Baldwin
  • B.G. Davis


  • Science


  • Science 377 (6604): eabm3125


  • 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.