Covalent inhibition of pro-apoptotic BAX.
Matthew W McHenryPeiwen ShiChristina M CamaraDaniel T CohenT Justin RettenmaierUtsarga AdhikaryMicah A GygiKa YangSteven P GygiThomas E WalesJohn R EngenJames A WellsLoren D WalenskyPublished in: Nature chemical biology (2024)
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.
Keyphrases
- cell death
- induced apoptosis
- endoplasmic reticulum stress
- oxidative stress
- cell cycle arrest
- signaling pathway
- high throughput
- squamous cell carcinoma
- ms ms
- fatty acid
- crispr cas
- radiation therapy
- small molecule
- protein protein
- rectal cancer
- mass spectrometry
- artificial intelligence
- liquid chromatography tandem mass spectrometry
- anti inflammatory
- molecular dynamics
- cancer therapy
- data analysis
- stress induced
- endoplasmic reticulum