{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["28(9)"],"submitter":["Wang J"],"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."],"journal":["iScience"],"pagination":["113309"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12396273"],"repository":["biostudies-literature"],"pubmed_title":["Molecular mechanisms underlying HRK interaction with BCL-XL and BCL-2 reveal specificity determinants for BH3 mimetics."],"pmcid":["PMC12396273"],"pubmed_authors":["Guo M","Dai S","Wei H","Wang J"],"additional_accession":[]},"is_claimable":false,"name":"Molecular mechanisms underlying HRK interaction with BCL-XL and BCL-2 reveal specificity determinants for BH3 mimetics.","description":"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.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Sep","modification":"2026-05-29T19:08:31.087Z","creation":"2026-05-18T03:07:42.164Z"},"accession":"S-EPMC12396273","cross_references":{"pubmed":["40894900"],"doi":["10.1016/j.isci.2025.113309"]}}