Fluorinated aromatic amino acids are sensitive 19 f NMR probes for bromodomain-ligand interactions

Neeraj K. Mishra, Andrew K. Urick, Stuart W.J. Ember, Ernst Schonbrunn, William C. Pomerantz

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We describe a 19 F NMR method for detecting bromodomain-ligand interactions using fluorine-labeled aromatic amino acids due to the conservation of aromatic residues in the bromodomain binding site. We test the sensitivity, accuracy, and speed of this method with small molecule ligands (+)-JQ1, BI2536, Dinaciclib, TG101348, and acetaminophen using three bromodomains Brd4, BrdT, and BPTF. Simplified 19 F NMR spectra allowed for simultaneous testing of multiple bromodomains to assess selectivity and identification of a new BPTF ligand. Fluorine labeling only modestly affected the Brd4 structure and function assessed by isothermal titration calorimetry, circular dichroism, and X-ray crystallography. The speed, ease of interpretation, and low concentration of protein needed for binding experiments affords a new method to discover and characterize both native and new ligands.

Original languageEnglish (US)
Pages (from-to)2755-2760
Number of pages6
JournalACS Chemical Biology
Issue number12
StatePublished - Dec 19 2014

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© 2014 American Chemical Society.


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