Angewandte Chemie International Edition · 2017 · 31 citations · 21 references
Life SciencesBiochemistryMolecular BiologyMolecular RecognitionProtein BiochemistryStructural BiologyGlycan StructureGlycan-protein InteractionsLigand BindingPolysaccharide StructureProtein StructureProtein-ligand BindingHeparin-binding ProteinsHeparin-protein InteractionsHydrophobic InteractionsMolecular Recognition ModelingMultidimensional Nmr SpectroscopyMycobacterium Tuberculosis InfectionMycobacterium Tuberculosis PathogenesisProtein-glycan Complex Structures
Abstract Heparin‐binding hemagglutinin (HBHA) is a 199 amino acid virulence factor at the envelope of Mycobacterium tuberculosis that contributes to latent tuberculosis. The binding of HBHA to respiratory epithelial cells, which leads to extrapulmonary dissemination of the pathogen, is mediated by cell‐surface heparan sulfate (HS). We report the structural characterization of the HBHA/HS complex by NMR spectroscopy. To develop a model for the molecular recognition, the first chemically synthesized uniformly 13 C‐ and 15 N‐labeled HS octasaccharide and a uniformly 13 C‐ and 15 N‐labeled form of HBHA were prepared. Residues 180–195 at the C‐terminal region of HBHA show large chemical shift perturbation upon association with the octasaccharide. Molecular dynamics simulations conforming to the multidimensional NMR data revealed key electrostatic and even hydrophobic interactions between the binding partners that may aid in the development of agents targeting the binding event.
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