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

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

Author information

1
Biomedical Research Center, KIST, Republic of Korea.

Abstract

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.

PMID:
20206602
DOI:
10.1016/j.bbrc.2010.03.002
[Indexed for MEDLINE]

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