Covalent Lipid Pocket Ligands Targeting p38α MAPK Mutants.
Angew Chem Int Ed Engl
; 56(43): 13232-13236, 2017 10 16.
Article
em En
| MEDLINE
| ID: mdl-28834017
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinazolinas
/
Proteína Quinase 14 Ativada por Mitógeno
/
Ligantes
Limite:
Humans
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Alemanha