8IQM

Structural basis of the specificity and interaction mechanism of Bmf binding to pro-survival proteins

Summary for 8IQM

• Entry DOI: 10.2210/pdb8iqm/pdb
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, Bcl2 modifying factor (3 entities in total)
• Functional Keywords: complex, apoptosis
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 20460.30

Authors

Wang, H.,Guo, M.,Wei, H.,Chen, Y. (deposition date: 2023-03-16, release date: 2023-08-23)

Primary citation

Wang, H.,Guo, M.,Wei, H.,Chen, Y.
Structural basis of the specificity and interaction mechanism of Bmf binding to pro-survival Bcl-2 family proteins.
Comput Struct Biotechnol J, 21:3760-3767, 2023

PubMed Abstract: The apoptotic pathway is regulated by protein-protein interactions between members of the Bcl-2 family. Pro-survival Bcl-2 family proteins act as cell guardians and protect cells against death. Selective binding and neutralization of BH3-only proteins with pro-survival Bcl-2 family proteins is critical for initiating apoptosis. In this study, the binding assay shows that the BH3 peptide derived from the BH3-only protein Bmf has a high affinity for the pro-survival proteins Bcl-2 and Bcl-xL, but a much lower affinity for Mcl-1. The complex structures of Bmf BH3 with Bcl-2, Bcl-xL and Mcl-1 reveal that the α-helical Bmf BH3 accommodates into the canonical groove of these pro-survival proteins, but the conformational changes and some interactions are different among the three complexes. Bmf BH3 forms conserved hydrophobic and salt bridge interactions with Bcl-2 and Bcl-xL, and also establishes several hydrogen bonds to support their binding. However, the highly conserved Asp-Arg salt bridge is not formed in the Mcl-1/Bmf BH3 complex, and few hydrogen bonds are observed. Furthermore, mutational analysis shows that substitutions of less-conserved residues in the α2-α3 region of these pro-survival Bcl-2 family proteins, as well as the highly conserved Arg, lead to significant changes in their binding affinity to Bmf BH3, while substitutions of less-conserved residues in Bmf BH3 have a more dramatic effect on its affinity to Mcl-1. This study provides structural insight into the specificity and interaction mechanism of Bmf BH3 binding to pro-survival Bcl-2 family proteins, and helps guide the design of BH3 mimics targeting pro-survival Bcl-2 family proteins.

PubMed: 37560128
DOI: 10.1016/j.csbj.2023.07.017

Experimental method

X-RAY DIFFRACTION (1.967 Å)