Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 56, Issue 42, Pages 12982-12986Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201707114
Keywords
chemical exchange saturation transfer; bromodomains; inhibitors; NMR spectroscopy; pseudocontact shifts
Categories
Funding
- Chinese Academy of Sciences [XDB08030302]
- Ministry of Science and Technology of China [2016YFA0500700, 2014CB910600]
- Natural Science Foundation of China [U1632153]
Ask authors/readers for more resources
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 F-19 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 F-19 PCSs were retrieved from F-19 chemical exchange saturation transfer (CEST) in the presence of the lanthanide-labeled protein, which was termed the F-19 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available