Identifying A Unified Numbering Scheme Across BCL-BH3 Structures Using the Knob-Socket Model
Poster Number
15
Faculty Mentor Name
Jerry Tsai, Tiffanie Jiang
Research or Creativity Area
Natural Sciences
Abstract
BH3 mimetics are sought after anti-cancer agents, because they reverse the inhibition of BAX and BAK apoptotic cell effectors and permit cell death of a cancerous cell. BH3 mimetics are designed to bind into the hydrophobic groove of the BCL-2 protein family that regulates apoptosis for healthy cells with pro-apoptotic and anti-apoptotic proteins. In order to identify which residues are responsible for affinity and specificity in the BCL-2 binding groove, a Knob-Socket analysis is utilized to computationally map out the important surfaces defined as 3 residue “sockets” that bind residues defined a a “knob” in the binding groove. From a Knob-Socket mapping of several BH3 ligands bound to various BCL-2 proteins, helices 3, 4, and 5 of BCL-2 are responsible for binding with BH3 ligands. Previous analysis revealed a conserved Gly to Gly packing between the ligand and helix 5 (H5) of BCL-2, but further analysis of this family of interactions reveals an alternate specificity of a conserved Leu-Leu between the ligand and H5. The Leu-Leu interaction between the ligand and H5 is shown to have conserved socket residues of Asn, Trp, Gly, and Arg at the turn of the helix. In relation to the conserved Gly, the Leu residue is set at position -4 with alanine as the other conserved residue at position 0. These findings enhance the understanding of BH3 and similar ligand domains that specifically interact with BCL-2 proteins. By identifying the key residues involved in BH3 binding, more potent BH3 mimetics can be developed as potential agents to induce apoptosis in cancer cells.
Location
University of the Pacific, DeRosa University Center
Start Date
26-4-2025 10:00 AM
End Date
26-4-2025 1:00 PM
Identifying A Unified Numbering Scheme Across BCL-BH3 Structures Using the Knob-Socket Model
University of the Pacific, DeRosa University Center
BH3 mimetics are sought after anti-cancer agents, because they reverse the inhibition of BAX and BAK apoptotic cell effectors and permit cell death of a cancerous cell. BH3 mimetics are designed to bind into the hydrophobic groove of the BCL-2 protein family that regulates apoptosis for healthy cells with pro-apoptotic and anti-apoptotic proteins. In order to identify which residues are responsible for affinity and specificity in the BCL-2 binding groove, a Knob-Socket analysis is utilized to computationally map out the important surfaces defined as 3 residue “sockets” that bind residues defined a a “knob” in the binding groove. From a Knob-Socket mapping of several BH3 ligands bound to various BCL-2 proteins, helices 3, 4, and 5 of BCL-2 are responsible for binding with BH3 ligands. Previous analysis revealed a conserved Gly to Gly packing between the ligand and helix 5 (H5) of BCL-2, but further analysis of this family of interactions reveals an alternate specificity of a conserved Leu-Leu between the ligand and H5. The Leu-Leu interaction between the ligand and H5 is shown to have conserved socket residues of Asn, Trp, Gly, and Arg at the turn of the helix. In relation to the conserved Gly, the Leu residue is set at position -4 with alanine as the other conserved residue at position 0. These findings enhance the understanding of BH3 and similar ligand domains that specifically interact with BCL-2 proteins. By identifying the key residues involved in BH3 binding, more potent BH3 mimetics can be developed as potential agents to induce apoptosis in cancer cells.
