8Y1Z

Crystal structure of the Mcl-1 in complex with a Short BH3 peptide of BAK

Summary for 8Y1Z

• Entry DOI: 10.2210/pdb8y1z/pdb
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, Short BH3 peptide from Bcl-2 homologous antagonist/killer (3 entities in total)
• Functional Keywords: mcl-1, bak, bh3, apoptosis
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 19649.28

Authors

Wang, H.,Guo, M.,Wei, H.,Chen, Y. (deposition date: 2024-01-25, release date: 2025-01-29, Last modification date: 2025-06-25)

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., 32:991-999, 2025

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: 39901037
DOI: 10.1038/s41418-025-01454-2

Experimental method

X-RAY DIFFRACTION (1.914 Å)