9LGU

Crystal structure of Bcl-xL in complex with stapled HRK peptide

Summary for 9LGU

• Entry DOI: 10.2210/pdb9lgu/pdb
• Descriptor: Bcl-2-like protein 1, Activator of apoptosis harakiri, MAGNESIUM ION (3 entities in total)
• Functional Keywords: bcl-2 family, mitochondrial apoptosis, bh3 mimetics, apoptosis
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 12
• Total formula weight: 164096.70

Authors

Wei, H.,Guo, M.,Wang, J. (deposition date: 2025-01-10, release date: 2025-08-06, Last modification date: 2025-09-17)

Primary citation

Wang, J.,Guo, M.,Dai, S.,Wei, H.
Molecular mechanisms underlying HRK interaction with BCL-XL and BCL-2 reveal specificity determinants for BH3 mimetics.
Iscience, 28:113309-113309, 2025

PubMed Abstract: BH3 mimetics targeting the BCL-2 family hold broad promise for cancer therapy. High similarity between the anti-apoptotic proteins BCL-XL and BCL-2 challenges the engineering of selective inhibitors. The BH3-only protein HRK is a natural selective inhibitor of BCL-XL and to a less extent of BCL-2. The detailed interaction mechanism remains elusive. Our structural and mutational analyses show that the discrepant conformational changes and non-conserved residues in the α2-α3 region are crucial for the preferential binding between BCL-XL and HRK. BCL-XL tolerates hydrophilic Thr33 or hydrophobic substitutions at the h1 position of HRK, whereas BCL-2 favors hydrophobic interactions, resulting in a weaker affinity for HRK. In addition, we design HRK-derived stapled peptides with improved helicity and activity against BCL-XL and BCL-2, and further elucidate the structural mechanism. Our findings reveal the binding specificity of HRK interactions with BCL-XL and BCL-2, and provide advanced insights into the development of BH3 mimetics.

PubMed: 40894900
DOI: 10.1016/j.isci.2025.113309

Experimental method

X-RAY DIFFRACTION (2.97 Å)