Abstract
To study the role of the BH3 domain in mediating pro-apoptotic and anti-apoptotic activities of Bcl-2 family members, we identified a series of novel small molecules (BH3Is) that inhibit the binding of the Bak BH3 peptide to Bcl-xL. NMR analyses revealed that BH3Is target the BH3-binding pocket of Bcl-xL. Inhibitors specifically block the BH3-domain-mediated heterodimerization between Bcl-2 family members in vitro and in vivo and induce apoptosis. Our results indicate that BH3-dependent heterodimerization is the key function of anti-apoptotic Bcl-2 family members and is required for the maintenance of cellular homeostasis.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Apoptosis / physiology*
-
BH3 Interacting Domain Death Agonist Protein
-
Blotting, Western
-
Carrier Proteins / metabolism
-
Caspases / metabolism
-
Cell Line
-
Cell Separation
-
Cytochrome c Group / metabolism
-
Dimerization
-
Flow Cytometry
-
Fluorescence Polarization / methods
-
Genes, Reporter
-
Humans
-
In Situ Nick-End Labeling
-
Magnetic Resonance Spectroscopy
-
Membrane Proteins / chemistry
-
Membrane Proteins / genetics
-
Membrane Proteins / metabolism*
-
Models, Molecular
-
Protein Binding
-
Protein Conformation
-
Protein Structure, Tertiary*
-
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
-
Proto-Oncogene Proteins c-bcl-2 / chemistry
-
Proto-Oncogene Proteins c-bcl-2 / metabolism*
-
Recombinant Fusion Proteins / metabolism
-
bcl-2 Homologous Antagonist-Killer Protein
-
bcl-X Protein
Substances
-
BAK1 protein, human
-
BCL2L1 protein, human
-
BH3 Interacting Domain Death Agonist Protein
-
BID protein, human
-
Carrier Proteins
-
Cytochrome c Group
-
Membrane Proteins
-
Proto-Oncogene Proteins c-bcl-2
-
Recombinant Fusion Proteins
-
bcl-2 Homologous Antagonist-Killer Protein
-
bcl-X Protein
-
Caspases