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

Amit Priyadarshi; Ankoor Roy; Key Sun Kim; Eunice Eun Kyeong Kim; Kwang Yeon Hwang

doi:10.1016/j.bbrc.2010.03.002

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

Amit Priyadarshi, Ankoor Roy, Key Sun Kim, Eunice Eun Kyeong Kim, Kwang Yeon Hwang

Department of Biosystems and Biotechnology

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

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 α1 and α2 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 μM. 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.

Original language	English
Pages (from-to)	515-521
Number of pages	7
Journal	Biochemical and biophysical research communications
Volume	394
Issue number	3
DOIs	https://doi.org/10.1016/j.bbrc.2010.03.002
Publication status	Published - 2010 Apr 9

Keywords

Apoptosis
Bcl-xl
Beclin
Gossypol
Mutation

ASJC Scopus subject areas

Biophysics
Biochemistry
Molecular Biology
Cell Biology

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

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 α1 and α2 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 Kd value of 0.9 μM. 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.",

keywords = "Apoptosis, Bcl-xl, Beclin, Gossypol, Mutation",

author = "Amit Priyadarshi and Ankoor Roy and Kim, {Key Sun} and Kim, {Eunice Eun Kyeong} and Hwang, {Kwang Yeon}",

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AU - Priyadarshi, Amit

AU - Roy, Ankoor

AU - Kim, Key Sun

AU - Kim, Eunice Eun Kyeong

AU - Hwang, Kwang Yeon

PY - 2010/4/9

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N2 - 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 α1 and α2 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 Kd value of 0.9 μM. 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.

AB - 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 α1 and α2 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 Kd value of 0.9 μM. 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.

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KW - Bcl-xl

KW - Beclin

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