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

Priyadarshi A, Roy A, Kim KS, Kim EE, Hwang KY
Biochem Biophys Res Commun 394 515-21 (2010)
Related entries: 3ihc, 3ihd, 3ihe, 3ihf, 3iig, 3iih, 3ilb

Cited: 8 times
EuropePMC logo PMID: 20206602

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 alpha1 and alpha2 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 microM. 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.

Reviews - 3ilc mentioned but not cited (2)

  1. The Structural Biology of Bcl-xL. Lee EF, Fairlie WD. Int J Mol Sci 20 E2234 (2019)
  2. A mechanistic view of enzyme evolution. Yang G, Miton CM, Tokuriki N. Protein Sci 29 1724-1747 (2020)


Articles citing this publication (6)

  1. The Bcl-2-Beclin 1 interaction in (-)-gossypol-induced autophagy versus apoptosis in prostate cancer cells. Lian J, Karnak D, Xu L. Autophagy 6 1201-1203 (2010)
  2. A natural BH3 mimetic induces autophagy in apoptosis-resistant prostate cancer via modulating Bcl-2-Beclin1 interaction at endoplasmic reticulum. Lian J, Wu X, He F, Karnak D, Tang W, Meng Y, Xiang D, Ji M, Lawrence TS, Xu L. Cell Death Differ 18 60-71 (2011)
  3. The BECN1 N-terminal domain is intrinsically disordered. Lee EF, Perugini MA, Pettikiriarachchi A, Evangelista M, Keizer DW, Yao S, Fairlie WD. Autophagy 12 460-471 (2016)
  4. BH3-mimetic gossypol-induced autophagic cell death in mutant BRAF melanoma cells with high expression of p21Cip¹.). Jang GH, Lee M. Life Sci 102 41-48 (2014)
  5. Dynamics of the BH3-Only Protein Binding Interface of Bcl-xL. Liu X, Beugelsdijk A, Chen J. Biophys J 109 1049-1057 (2015)
  6. Defective autophagy in multidrug resistant cells may lead to growth inhibition by BH3-mimetic gossypol. Ahn JH, Jang GH, Lee M. J Cell Physiol 228 1496-1505 (2013)


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