Covalent Lipid Pocket Ligands Targeting p38α MAPK Mutants.
Mike BührmannJulia HardickJörn WeisnerLena QuambuschDaniel RauhPublished in: Angewandte Chemie (International ed. in English) (2017)
A chemical genetic approach is presented to covalently target a unique lipid binding pocket in the protein kinase p38α, whose function is not yet known. Based on a series of cocrystal structures, a library of 2-arylquinazolines that were decorated with electrophiles were designed and synthesized to covalently target tailored p38α mutants containing artificially introduced cysteine residues. Matching protein-ligand pairs were identified by MS analysis and further validated by MS/MS studies and protein crystallography. The covalent ligands that emerged from this approach showed excellent selectivity towards a single p38α mutant and will be applicable as suitable probes in future studies of biological systems to dissect the function of the lipid pocket by means of pharmacological perturbations.
Keyphrases
- ms ms
- fatty acid
- protein kinase
- wild type
- protein protein
- case control
- living cells
- multiple sclerosis
- small molecule
- mass spectrometry
- high resolution
- amino acid
- gene expression
- smoking cessation
- liquid chromatography tandem mass spectrometry
- copy number
- dna methylation
- current status
- transcription factor
- photodynamic therapy