{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["McHenry MW"],"funding":["U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)","NIAID NIH HHS","U.S. Department of Health & Human Services | NIH | National Cancer Institute","NHLBI NIH HHS","U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute","NCI NIH HHS","U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)","NIGMS NIH HHS","National Science Foundation"],"pagination":["1022-1032"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11252247"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["20(8)"],"pubmed_abstract":["BCL-2-associated X protein (BAX) is a promising therapeutic target for activating or restraining apoptosis in diseases of pathologic cell survival or cell death, respectively. In response to cellular stress, BAX transforms from a quiescent cytosolic monomer into a toxic oligomer that permeabilizes the mitochondria, releasing key apoptogenic factors. The mitochondrial lipid trans-2-hexadecenal (t-2-hex) sensitizes BAX activation by covalent derivatization of cysteine 126 (C126). In this study, we performed a disulfide tethering screen to discover C126-reactive molecules that modulate BAX activity. We identified covalent BAX inhibitor 1 (CBI1) as a compound that selectively derivatizes BAX at C126 and inhibits BAX activation by triggering ligands or point mutagenesis. Biochemical and structural analyses revealed that CBI1 can inhibit BAX by a dual mechanism of action: conformational constraint and competitive blockade of lipidation. These data inform a pharmacologic strategy for suppressing apoptosis in diseases of unwanted cell death by covalent targeting of BAX C126."],"journal":["Nature chemical biology"],"pubmed_title":["Covalent inhibition of pro-apoptotic BAX."],"pmcid":["PMC11252247"],"funding_grant_id":["T32 HL007574","R01 AI070292","5T32HL007574","R35 CA197583","F30 CA275293","R35CA197583","R01 GM067945"],"pubmed_authors":["Engen JR","McHenry MW","Yang K","Shi P","Walensky LD","Gygi MA","Camara CM","Wales TE","Cohen DT","Gygi SP","Rettenmaier TJ","Adhikary U","Wells JA"],"additional_accession":[]},"is_claimable":false,"name":"Covalent inhibition of pro-apoptotic BAX.","description":"BCL-2-associated X protein (BAX) is a promising therapeutic target for activating or restraining apoptosis in diseases of pathologic cell survival or cell death, respectively. In response to cellular stress, BAX transforms from a quiescent cytosolic monomer into a toxic oligomer that permeabilizes the mitochondria, releasing key apoptogenic factors. The mitochondrial lipid trans-2-hexadecenal (t-2-hex) sensitizes BAX activation by covalent derivatization of cysteine 126 (C126). In this study, we performed a disulfide tethering screen to discover C126-reactive molecules that modulate BAX activity. We identified covalent BAX inhibitor 1 (CBI1) as a compound that selectively derivatizes BAX at C126 and inhibits BAX activation by triggering ligands or point mutagenesis. Biochemical and structural analyses revealed that CBI1 can inhibit BAX by a dual mechanism of action: conformational constraint and competitive blockade of lipidation. These data inform a pharmacologic strategy for suppressing apoptosis in diseases of unwanted cell death by covalent targeting of BAX C126.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Aug","modification":"2026-03-18T13:35:04.65Z","creation":"2025-08-18T09:54:19.607Z"},"accession":"S-EPMC11252247","cross_references":{"pubmed":["38233584"],"doi":["10.1038/s41589-023-01537-6"]}}