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 Eun Kyeong
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 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.
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 - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 3
ER -
