Structural insights into mouse anti-apoptotic Bcl-xl reveal affinity for Beclin 1 and gossypol

Biochem Biophys Res Commun. 2010 Apr 9;394(3):515-21. doi: 10.1016/j.bbrc.2010.03.002. Epub 2010 Mar 4.


This study reports the crystal structures of Bcl-xl wild type and three Bcl-xl mutants (Y101A, F105A, and R139A) with amino acid substitutions in the hydrophobic groove of the Bcl-xl BH3 domain. An additional 12 ordered residues were observed in a highly flexible loop between the alpha1 and alpha2 helices, and were recognized as an important deamidation site for the regulation of apoptosis. The autophagy-effector protein, Beclin 1, contains a novel BH3 domain (residues 101-125), which binds to the surface cleft of Bcl-xl, as confirmed by nuclear magnetic resonance (NMR) spectroscopy and analytical gel-filtration results. Gossypol, a potent inhibitor of Bcl-xl, had a K(d) value of 0.9 microM. In addition, the structural and biochemical analysis of five Bcl-xl substitution mutants will provide structural insights into the design and development of anti-cancer drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Antineoplastic Agents / chemistry
  • Apoptosis Regulatory Proteins / chemistry*
  • Beclin-1
  • Chromatography, Gel
  • Crystallography, X-Ray
  • Drug Design
  • Gossypol / chemistry*
  • Mice
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • bcl-X Protein / antagonists & inhibitors*
  • bcl-X Protein / chemistry*
  • bcl-X Protein / genetics


  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Bcl2l1 protein, mouse
  • Beclin-1
  • Becn1 protein, mouse
  • bcl-X Protein
  • Gossypol