Structural insights for selective disruption of Beclin 1 binding to Bcl-2.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
24 10 2023
24 10 2023
Historique:
received:
08
09
2023
accepted:
16
10
2023
medline:
27
10
2023
pubmed:
25
10
2023
entrez:
24
10
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37875561
doi: 10.1038/s42003-023-05467-w
pii: 10.1038/s42003-023-05467-w
pmc: PMC10598227
doi:
Substances chimiques
Apoptosis Regulatory Proteins
0
bcl-2-Associated X Protein
0
Beclin-1
0
Membrane Proteins
0
BCL2 protein, human
0
BECN1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1080Subventions
Organisme : NIH HHS
ID : S10 OD018027
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI142784
Pays : United States
Informations de copyright
© 2023. Springer Nature Limited.
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