Structural insights for selective disruption of Beclin 1 binding to Bcl-2.
Commun Biol
; 6(1): 1080, 2023 10 24.
Article
em En
| MEDLINE
| ID: mdl-37875561
ABSTRACT
Stimulation of autophagy could provide powerful therapies for multiple diseases, including cancer and neurodegeneration. An attractive drug target for this purpose is Bcl-2, which inhibits autophagy by binding to the Beclin 1 BH3-domain. However, compounds that preclude Beclin 1/Bcl-2 binding might also induce apoptosis, which is inhibited by binding of Bcl-2 to BH3-domains of pro-apoptosis factors such as Bax. Here we describe the NMR structure of Bcl-2 bound to 35, a compound that we recently found to inhibit Beclin 1/Bcl-2 binding more potently than Bax/Bcl-2 binding. The structure shows that 35 binds at one end of the BH3-binding groove of Bcl-2. Interestingly, much of the 35-binding site is not involved in binding to Bcl-2 inhibitors described previously and mediates binding to Beclin 1 but not Bax. The structure suggests potential avenues to design compounds that disrupt Beclin 1/Bcl-2 binding and stimulate autophagy without inducing apoptosis.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Reguladoras de Apoptose
/
Proteínas de Membrana
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article