ArticleiScience2025
Molecular mechanisms underlying HRK interaction with BCL-XL and BCL-2 reveal specificity determinants for BH3 mimetics.
Article in iScience, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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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.
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