8Y20
Crystal structure of the Mcl-1 in complex with A-1210477
This is a non-PDB format compatible entry.
Summary for 8Y20
| Entry DOI | 10.2210/pdb8y20/pdb |
| Related PRD ID | PRD_900001 |
| Descriptor | Maltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, A-1210477, ... (4 entities in total) |
| Functional Keywords | mcl-1, bak, bh3, apoptosis |
| Biological source | Escherichia coli O157:H7 More |
| Total number of polymer chains | 1 |
| Total formula weight | 58418.20 |
| Authors | |
| Primary citation | Wei, H.,Wang, H.,Xiang, S.,Wang, J.,Qu, L.,Chen, X.,Guo, M.,Lu, X.,Chen, Y. Deciphering molecular specificity in MCL-1/BAK interaction and its implications for designing potent MCL-1 inhibitors. Cell Death Differ., 2025 Cited by PubMed Abstract: The intricate interplay among BCL-2 family proteins governs mitochondrial apoptosis, with the anti-apoptotic protein MCL-1 primarily exerting its function by sequestering the pore-forming effector BAK. Understanding the MCL-1/BAK complex is pivotal for the sensitivity of cancer cells to BH3 mimetics, yet the precise molecular mechanism underlying their interaction remains elusive. Herein, we demonstrate that a canonical BH3 peptide from BAK inadequately binds to MCL-1 proteins, whereas an extended BAK-BH3 peptide with five C-terminal residues exhibits a remarkable 65-fold increase in affinity. By elucidating the complex structures of MCL-1 bound to these two BAK-BH3 peptides at 2.08 Å and 1.98 Å resolutions, we uncover their distinct binding specificities. Notably, MCL-1 engages in critical hydrophobic interactions with the extended BAK-BH3 peptide, particularly at an additional p5 sub-pocket, featuring a π-π stacking interaction between MCL-1 Phe319 and BAK Tyr89. Mutations within this p5 sub-pocket substantially disrupt the MCL-1/BAK protein-protein interaction. Furthermore, the p5 sub-pocket of MCL-1 significantly influences the efficacy of MCL-1 inhibitors. Overall, our findings elucidate the molecular specificity underlying MCL-1 binding to BAK and underscore the significance of the p5 hydrophobic sub-pocket in their high-affinity interaction, thus providing novel insights for the development of BH3 mimetics targeting the MCL-1/BAK interaction as potential therapeutics for cancer treatment. PubMed: 39901037DOI: 10.1038/s41418-025-01454-2 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.23 Å) |
Structure validation
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