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Human Bcl2-A1 in complex with BIM-BH3 peptide

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PDB Code 2VM6 Target Class Apoptosis Target BCL2A1 Alias ACC-1, ACC-2, BCL2A1, BCL2L5, BFL1, GRS, HBPA1 Disease Area/Function cancer, signalling, neurobiology Date Deposited Jan 23 2008 Authors M.D. HERMAN, L.LEHTIO, C.H.ARROWSMITH, H.BERGLUND, R.D.BUSAM, R.COLLINS, L.G.DAHLGREN, A.EDWARDS, S.FLODIN, A.FLORES, S.GRASLUND, M.HAMMARSTROM, I.JOHANSSON, A.KALLAS, T.KOTENYOVA, L.LEHTIO, M.MOCHE, M.E.NILSSON, P.NORDLUND, T.NYMAN, C.PERSSON, J.SAGEMARK, L.SVENSSON, A.G.THORSELL, S.VAN DEN BERG, J.WEIGELT, M.WELIN

About this structure

The Bcl-2 family of proteins is composed of both proapoptotic and antiapoptotic members that cooperate through a complex series of protein-protein interactions to mediate the mitochondrial apoptotic pathway (1,2). The proapoptotic proteins can be divided into two groups; multidomain proteins that contain three Bcl homology (BH) domains (BH1-BH3) and those that contain a single BH3 domain, called BH3-only proteins, such as Bim. Antiapoptotic Bcl-2 family members contain three or four BH domains and include Bcl-2, Bcl-xL, Bcl-w, Mcl-1, and Bcl2-A1. These proteins exert their protective effects partly by binding directly to and sequestering their proapoptotic counterparts. Due to their central role in inhibiting apoptosis, antiapoptotic proteins are attractive targets for therapeutic intervention, and rational drug development of antagonists holds promise for the selective induction of programmed cell death in cancer cells(3).

In the 2.2 Å structure of the Bcl2-A1:BimBH3 complex, Bcl2-A1 displays the conservative fold of Bcl-2 family members, consisting of two central α-helices containing predominantly hydrophobic residues and arranged in an antiparallel fashion, surrounded by amphipathic helices. The three functionally important BH1-BH3 regions are in close spatial proximity and form an elongated hydrophobic cleft, which represent the binding site for Bim .The structure of the human Bcl2-A1:Bim complex contributes to the growing knowledge of interaction specificity in the Bcl-2 family of apoptotic regulators (4).

References

  • Petros A. M. el al., Biochim. Biophys. Acta, 1644, 83-44 (2004)
  • Huang D.C. et al., Cell, 103, 839-42, (2000)
  • Fesik, et al., Nat. Rev. Cancer,5, 876-85 (2005)
  • Herman MD et al. FEBS Lett. 2008 Sep 20. [Epub ahead of print]