Bitopic Inhibition of ATP and Substrate Binding in Ser/Thr Kinases through a Conserved Allosteric Mechanism.
Biochemistry
; 57(45): 6387-6390, 2018 11 13.
Article
em En
| MEDLINE
| ID: mdl-30339352
ABSTRACT
Protein kinases achieve substrate selective phosphorylation through their conformational flexibility and dynamic interaction with the substrate. Designing substrate selective or kinase selective small molecule inhibitors remains a challenge because of a lack of understanding of the dynamic mechanism by which substrates are selected by the kinase. Using a combination of all-atom molecular dynamics simulations and FRET sensors, we have delineated an allosteric mechanism that results in interaction among the DFG motif, G-loop, and activation loop and structurally links the nucleotide and substrate binding interfaces in protein kinase Cα and three other Ser/Thr kinases. ATP-competitive staurosporine analogues engage this allosteric switch region located just outside the ATP binding site to displace substrate binding to varying degrees. These inhibitors function as bitopic ligands by occupying the ATP binding site and interacting with the allosteric switch region. The conserved mechanism identified in this study can be exploited to select and design bitopic inhibitors for kinases.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Trifosfato de Adenosina
/
Inibidores de Proteínas Quinases
/
Proteína Quinase C-alfa
Limite:
Humans
Idioma:
En
Revista:
Biochemistry
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos