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Fluorine Pseudocontact Shifts Used for Characterizing the Protein–Ligand Interaction Mode in the Limit of NMR Intermediate Exchange

  • [设施]:上海设施
  • [期刊/会议名称]:Angew Chem Int Ed Engl.
  • [摘要]:The characterization of protein–ligand interaction modes becomes recalcitrant in the NMR intermediate exchange regime as the interface resonances are broadened beyond detection. Here, we determined the 19F low-populated bound-state pseudocontact shifts (PCSs) of mono- and di-fluorinated inhibitors of the BRM bromodomain using a highly skewed protein/ligand ratio. The bound-state 19F PCSs were retrieved from 19F chemical exchange saturation transfer (CEST) in the presence of the lanthanide-labeled protein, which was termed the 19F PCS-CEST approach. These PCSs enriched in spatial information enabled the identification of best-fitting poses, which agree well with the crystal structure of a more soluble analog in complex with the BRM bromodomain. This approach fills the gap of the NMR structural characterization of lead-like inhibitors with moderate affinities to target proteins, which are essential for structure-guided hit-to-lead evolution.
  • [发表日期]:2017
  • [第一作者]:高佳
  • [第一作者单位]:中国科学技术大学
  • [通讯作者]:阮科
  • [通讯作者单位]:中国科学技术大学
  • [论文类型]:0
  • [期刊分类]:SCI1区
  • [学科分类]:化学
  • [影响因子]:11.994
  • [关键词]:NMR spectroscopy; bromodomains; chemical exchange saturation transfer; inhibitors; pseudocontact shifts
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