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Dual Labeling of the CBP/p300 KIX Domain for 19 F NMR Leads to Identification of a New Small-Molecule Binding Site.
- Source :
-
Chembiochem : a European journal of chemical biology [Chembiochem] 2018 May 04; Vol. 19 (9), pp. 963-969. Date of Electronic Publication: 2018 Apr 06. - Publication Year :
- 2018
-
Abstract
- Protein-Observed Fluorine NMR (PrOF NMR) spectroscopy is an emerging technique for screening and characterizing small-molecule-protein interactions. The choice of which amino acid to label for PrOF NMR can be critical for analysis. Here we report the first use of a protein containing two different fluoroaromatic amino acids for NMR studies. Using the KIX domain of the CBP/p300 as a model system, we examine ligand binding of several small-molecule compounds elaborated from our previous fragment screen and identify a new ligand binding site distinct from those used by native transcription factors. This site was further supported by computational modeling (FTMap and Schrödinger) and <superscript>1</superscript> H, <superscript>15</superscript> N HSQC/HMQC NMR spectroscopy. Metabolic labeling with multiple fluorinated amino acids provides useful probes for further studying ligand binding and has led to new insight for allosterically regulating transcription-factor protein interactions with small-molecule ligands.<br /> (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Animals
Binding Sites drug effects
CREB-Binding Protein chemistry
CREB-Binding Protein metabolism
Cyclic AMP Response Element-Binding Protein chemistry
Cyclic AMP Response Element-Binding Protein metabolism
Fluorine analysis
Humans
Mice
Models, Molecular
Nuclear Magnetic Resonance, Biomolecular
Protein Binding drug effects
Protein Domains drug effects
Protein Interaction Maps drug effects
Rats
Small Molecule Libraries chemistry
p300-CBP Transcription Factors chemistry
Small Molecule Libraries pharmacology
p300-CBP Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1439-7633
- Volume :
- 19
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Chembiochem : a European journal of chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 29430847
- Full Text :
- https://doi.org/10.1002/cbic.201700686