The structure of BCL-2 with Venetoclax

3D Model

BCL-2 proteins are a group of regulator proteins control the cell death. BCL-2 protein has a motif of two hydrophobic α-helices surrounded by 6-7 amphipathic α-helices. The binding site for those proapoptotic proteins is formed by 4 of the amphipathic helices which can generate a hydrophobic groove. They also have a BH3 domain which is a potent death domain and is important in protein-protein interactions. The interactions in P2 and P4, two hydrophobic pockets, and the electrostatic interaction between aspartic acid and arginine residues on the proapoptotic and antiapoptotic proteins mediate the binding to the BCL-2 proteins. The P2 pocket is a critical determinant for the selectivity of BH3 peptides. Adjacent residues A100 and D103 define boundaries of the P4 pocket, and the F104 side chain separates the P2 and P4 pockets of BCL-2. In addition, the nitrogen atom of the azaindole formed a hydrogen bond with Asp103 of BCL-2.