Editorial Volume 7, Issue 10 pp 748—749

Figure 1. Two functional domains, the BH4 domain and the hydrophobic cleft, are important for Bcl-2's anti-apoptotic function. The transmembrane (TM) domain anchors Bcl-2 in ER and mitochondrial membranes. The BH4 domain suppresses apoptosis by binding and inhibiting Bax (in mitochondria) and IP3 receptors (in ER). The hydrophobic cleft interacts with several pro-apoptotic Bcl-2 family members, including Bax/Bak and BH3-only proteins like Bim. BH3 mimetics, like ABT-737, ABT-263 and ABT-199, target the hydrophobic cleft of Bcl-2 and release Bim, leading to Bim-mediated activation of Bax/Bak and inducing apoptosis. Furthermore, BIRD-2 (Bcl-2/IP₃ receptor Disruptor-2) and BDA -366 have been developed to antagonize Bcl-2 via its BH4 domain leading to apoptosis although via different mechanisms. BIRD-2 provokes pro-apoptotic Ca²⁺ signaling, while BDA-366 causes a conformational change in Bcl-2, resulting in the exposure of its BH3 domain, which will activate Bax