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Title | Structural basis of BAK sequestration by MCL-1 in apoptosis. |
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Journal, issue, pages | Mol Cell, Vol. 85, Issue 8, Page 1606-1623.e10, Year 2025 |
Publish date | Apr 17, 2025 |
![]() | Shagun Srivastava / Giridhar Sekar / Adedolapo Ojoawo / Anup Aggarwal / Elisabeth Ferreira / Emiko Uchikawa / Meek Yang / Christy R Grace / Raja Dey / Yi-Lun Lin / Cristina D Guibao / Seetharaman Jayaraman / Somnath Mukherjee / Anthony A Kossiakoff / Bin Dong / Alexander Myasnikov / Tudor Moldoveanu / ![]() ![]() |
PubMed Abstract | Apoptosis controls cell fate, ensuring tissue homeostasis and promoting disease when dysregulated. The rate-limiting step in apoptosis is mitochondrial poration by the effector B cell lymphoma 2 (BCL- ...Apoptosis controls cell fate, ensuring tissue homeostasis and promoting disease when dysregulated. The rate-limiting step in apoptosis is mitochondrial poration by the effector B cell lymphoma 2 (BCL-2) family proteins BAK and BAX, which are activated by initiator BCL-2 homology 3 (BH3)-only proteins (e.g., BIM) and inhibited by guardian BCL-2 family proteins (e.g., MCL-1). We integrated structural, biochemical, and pharmacological approaches to characterize the human prosurvival MCL-1:BAK complex assembled from their BCL-2 globular core domains. We reveal a canonical interaction with BAK BH3 bound to the hydrophobic groove of MCL-1 and disordered and highly dynamic BAK regions outside the complex interface. We predict similar conformations of activated effectors in complex with other guardians or effectors. The MCL-1:BAK complex is a major cancer drug target. We show that MCL-1 inhibitors are inefficient in neutralizing the MCL-1:BAK complex, requiring high doses to initiate apoptosis. Our study underscores the need to design superior clinical candidate MCL-1 inhibitors. |
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Methods | EM (single particle) / X-ray diffraction |
Resolution | 1.49 - 3.34 Å |
Structure data | EMDB-45803, PDB-9cph: ![]() PDB-9cpe: ![]() PDB-9cpf: ![]() PDB-9cpn: |
Chemicals | ![]() ChemComp-HOH: |
Source |
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![]() | APOPTOSIS / Anti-apoptosis / Mitochondrial poration / BCL-2 family / Cell fate |