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The chemical diversity and structure-based discovery of allosteric modulators for the PIF-pocket of protein kinase PDK1.
J Enzyme Inhib Med Chem ; 34(1): 361-374, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30734603
ABSTRACT
Phosphoinositide-dependent protein kinase-1 (PDK1) is an important protein in mediating the PI3K-AKT pathway and is thus identified as a promising target. The catalytic activity of PDK1 is tightly regulated by allosteric modulators, which bind to the PDK1 Interacting Fragment (PIF) pocket of the kinase domain that is topographically distinct from the orthosteric, ATP binding site. Allosteric modulators by attaching to the less conserved PIF-pocket have remarkable advantages such as higher selectivity, less side effect, and lower toxicity. Targeting allosteric PIF-pocket of PDK1 has become the focus of recent attention. In this review, we summarise the current advances in the structure-based discovery of PDK1 allosteric modulators. We will first present the three-dimensional structure of PDK1 and illustrate the allosteric regulatory mechanism of PDK1 through the modulation of the PIF-pocket. Then, the recent advances of PDK1 allosteric modulators targeting the PIF-pocket will be recapitulated detailly according to the structural similarity of allosteric modulators.
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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Proteínas Serina-Treonina Quinases / Regulação Alostérica / Descoberta de Drogas Limite: Humanos Idioma: Inglês Revista: J Enzyme Inhib Med Chem Assunto da revista: Bioquímica / Química Ano de publicação: 2019 Tipo de documento: Artigo País de afiliação: China