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

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

Research output: Contribution to journalArticle

12 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 languageEnglish
Pages (from-to)515-521
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume394
Issue number3
DOIs
Publication statusPublished - 2010 Apr 9

Fingerprint

Gossypol
Autophagy
Amino Acid Substitution
Gel Chromatography
Substitution reactions
Magnetic Resonance Spectroscopy
Apoptosis
Pharmaceutical Preparations
Nuclear magnetic resonance spectroscopy
Neoplasms
Crystal structure
Gels
Amino Acids
Proteins
Beclin-1

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 journalArticle

Priyadarshi, Amit ; Roy, Ankoor ; Kim, Key Sun ; Kim, Eunice EunKyeong ; Hwang, Kwang Yeon. / Structural insights into mouse anti-apoptotic Bcl-xl reveal affinity for Beclin 1 and gossypol. In: Biochemical and Biophysical Research Communications. 2010 ; Vol. 394, No. 3. pp. 515-521.
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