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PMID: 11175750 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL.

Nature cell biology ·Vol. 3 ·No. 2 ·2001-02-00 ·Pages 173-82

Degterev A, Lugovskoy A, Cardone M, Mulley B, Wagner G, Mitchison T, Yuan J

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.

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,genetics,metabolism Models, Molecular Protein Binding Protein Conformation Protein Structure, Tertiary Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors,chemistry,metabolism Recombinant Fusion Proteins/metabolism bcl-2 Homologous Antagonist-Killer Protein bcl-X Protein

Chemicals

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

Authors & Affiliations

7 authors, click to expand affiliations / ORCID

Degterev A

Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.

Lugovskoy A

Cardone M

Mulley B

Wagner G

Mitchison T

Yuan J

Article Info

Journal

Nature cell biology

Abbr.

Nat Cell Biol

ISSN

1465-7392

DOI

10.1038/35055085

Published

2001-02-00

Pages

173-82

Language

English

Region

England

NLM ID

100890575

Subset

Corrections

CommentIn

PMID: 11175758

External Links

PubMed source DOI: 10.1038/35055085 View journal details

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Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL.

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