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 | |
| Publication status | Published - 2010 Apr 9 |
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Keywords
- Apoptosis
- Bcl-xl
- Beclin
- Gossypol
- Mutation
ASJC Scopus subject areas
- Biochemistry
- Biophysics
- Cell Biology
- Molecular Biology
Cite this
Structural insights into mouse anti-apoptotic Bcl-xl reveal affinity for Beclin 1 and gossypol. / Priyadarshi, Amit; Roy, Ankoor; Kim, Key Sun; Kim, Eunice EunKyeong; Hwang, Kwang Yeon.
In: Biochemical and Biophysical Research Communications, Vol. 394, No. 3, 09.04.2010, p. 515-521.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Structural insights into mouse anti-apoptotic Bcl-xl reveal affinity for Beclin 1 and gossypol
AU - Priyadarshi, Amit
AU - Roy, Ankoor
AU - Kim, Key Sun
AU - Kim, Eunice EunKyeong
AU - Hwang, Kwang Yeon
PY - 2010/4/9
Y1 - 2010/4/9
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 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.
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 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.
KW - Apoptosis
KW - Bcl-xl
KW - Beclin
KW - Gossypol
KW - Mutation
UR - http://www.scopus.com/inward/record.url?scp=77950518734&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77950518734&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2010.03.002
DO - 10.1016/j.bbrc.2010.03.002
M3 - Article
C2 - 20206602
AN - SCOPUS:77950518734
VL - 394
SP - 515
EP - 521
JO - The BMJ
JF - The BMJ
SN - 0730-6512
IS - 3
ER -