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Bohari, Mohammad H.; Yu, Xing; Kishor, Chandan; Patel, Brijesh; Go, Rob Marc; Eslampanah Seyedi, Hadieh A.; Vinik, Yaron; Grice, I. Darren; Zick, Yehiel; Blanchard, Helen

Structure‐Based Design of a Monosaccharide Ligand Targeting Galectin‐8

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  • Medientyp: E-Artikel
  • Titel: Structure‐Based Design of a Monosaccharide Ligand Targeting Galectin‐8
  • Beteiligte: Bohari, Mohammad H.; Yu, Xing; Kishor, Chandan; Patel, Brijesh; Go, Rob Marc; Eslampanah Seyedi, Hadieh A.; Vinik, Yaron; Grice, I. Darren; Zick, Yehiel; Blanchard, Helen
  • Erschienen: Wiley, 2018
  • Erschienen in: ChemMedChem
  • Sprache: Englisch
  • DOI: 10.1002/cmdc.201800224
  • ISSN: 1860-7179; 1860-7187
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>Galectin‐8 is a β‐galactoside‐recognising protein that has a role in the regulation of bone remodelling and is an emerging new target for tackling diseases with associated bone loss. We have designed and synthesised methyl 3‐<jats:italic>O</jats:italic>‐[1‐carboxyethyl]‐β‐<jats:sc>d</jats:sc>‐galactopyranoside (compound <jats:bold>6</jats:bold>) as a ligand to target the N‐terminal domain of galectin‐8 (galectin‐8<jats:italic>N</jats:italic>). Our design involved molecular dynamics (MD) simulations that predicted <jats:bold>6</jats:bold> to mimic the interactions made by the galactose ring as well as the carboxylic acid group of 3′‐<jats:italic>O</jats:italic>‐sialylated lactose (3′‐SiaLac), with galectin‐8<jats:italic>N</jats:italic>. Isothermal titration calorimetry (ITC) determined that the binding affinity of galectin‐8<jats:italic>N</jats:italic> for <jats:bold>6</jats:bold> was 32.8 μ<jats:sc>m</jats:sc>, whereas no significant affinity was detected for the C‐terminal domain of galectin‐8 (galectin‐8<jats:italic>C</jats:italic>). The crystal structure of the galectin‐8<jats:italic>N</jats:italic>–<jats:bold>6</jats:bold> complex validated the predicted binding conformation and revealed the exact protein–ligand interactions that involve evolutionarily conserved amino acids of galectin and also those unique to galectin‐8<jats:italic>N</jats:italic> for recognition. Overall, we have initiated and demonstrated a rational ligand design campaign to develop a monosaccharide‐based scaffold as a binder of galectin‐8.</jats:p>