Structural insights into mouse anti-apoptotic Bcl-xl reveal affinity for Beclin 1 and gossypol
- Biomedical Research Center, KIST (Korea, Republic of)
- Centre for Neural Sciences, KIST, Seoul 136-791 (Korea, Republic of)
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 {alpha}1 and {alpha}2 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{sub d} value of 0.9 {mu}M. 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.
- OSTI ID:
- 22202452
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 394, Issue 3; Other Information: Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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