PXD040917

PXD040917 is an original dataset announced via ProteomeXchange.

Dataset Summary

Title	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). Here, 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 the physiologic ligand tBID and 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. Hydrogen deuterium exchange mass spectrometry (HDX MS) showed that CBI1 derivatization of BAX C126 reversed the conformational changes caused by the auto-activating mutant F116A These data inform a pharmacologic strategy for blocking apoptosis in diseases of unwanted cell death by covalent targeting of BAX C126.
HostingRepository	PRIDE
AnnounceDate	2024-01-19
AnnouncementXML	Submission_2024-01-19_06:28:25.361.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	John R. Engen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Synapt MS

Dataset History

Revision	Datetime	Status	ChangeLog Entry
0	2023-03-16 12:21:17	ID requested
⏵ 1	2024-01-19 06:28:26	announced

Publication List

McHenry MW, Shi P, Camara CM, Cohen DT, Rettenmaier TJ, Adhikary U, Gygi MA, Yang K, Gygi SP, Wales TE, Engen JR, Wells JA, Walensky LD, Covalent inhibition of pro-apoptotic BAX. Nat Chem Biol, ():(2024) [pubmed]
10.1038/s41589-023-01537-6;

McHenry MW, Shi P, Camara CM, Cohen DT, Rettenmaier TJ, Adhikary U, Gygi MA, Yang K, Gygi SP, Wales TE, Engen JR, Wells JA, Walensky LD, Covalent inhibition of pro-apoptotic BAX. Nat Chem Biol, ():(2024) [pubmed]

10.1038/s41589-023-01537-6;

Keyword List

submitter keyword: BAX
HDX-MS
hydrogen/deuterium exchange mass spectrometry
covalent inhibitor

submitter keyword: BAX

HDX-MS

hydrogen/deuterium exchange mass spectrometry

covalent inhibitor

Contact List

John R. Engen
contact affiliation	Department of Chemistry & Chemical Biology, Northeastern University
contact email	j.engen@northeastern.edu
lab head
John R. Engen
contact affiliation	Northeastern University
contact email	j.engen@northeastern.edu
dataset submitter

Full Dataset Link List

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/01/PXD040917
PRIDE project URI

Dataset FTP location
NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/01/PXD040917

PRIDE project URI

Repository Record List

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