9CPN

Structural basis of BAK sequestration by MCL-1 and consequences for apoptosis initiation

Summary for 9CPN

• Entry DOI: 10.2210/pdb9cpn/pdb
• Related PRD ID: PRD_900001
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, Bcl-2 homologous antagonist/killer, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: anti-apoptosis, mitochondrial poration, bcl-2 family, cell fate, apoptosis
• Biological source: synthetic construct; More
• Total number of polymer chains: 8
• Total formula weight: 240311.59

Authors

Aggarwal, A.,Jayaraman, S.,Dey, R.,Moldoveanu, T. (deposition date: 2024-07-18, release date: 2025-06-04)

Primary citation

Srivastava, S.,Sekar, G.,Ojoawo, A.,Aggarwal, A.,Ferreira, E.,Uchikawa, E.,Yang, M.,Grace, C.R.,Dey, R.,Lin, Y.L.,Guibao, C.D.,Jayaraman, S.,Mukherjee, S.,Kossiakoff, A.A.,Dong, B.,Myasnikov, A.,Moldoveanu, T.
Structural basis of BAK sequestration by MCL-1 in apoptosis.
Mol.Cell, 85:1606-1623.e10, 2025

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-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.

PubMed: 40187349
DOI: 10.1016/j.molcel.2025.03.013

Experimental method

X-RAY DIFFRACTION (1.89 Å)