PXD053077-1

PXD053077 is an original dataset announced via ProteomeXchange.

Title	Protein-directed ABPP describing proteome-wide reactivities of WX-02-520 and WX-02-521 probes
Description	More than half of the ∼20,000 protein-encoding human genes have at least one paralog. Chemical proteomics has uncovered many electrophile-sensitive cysteines that are exclusive to a subset of paralogous proteins. Here, we explore whether such covalent compound-cysteine interactions can be used to discover ligandable pockets in paralogs that lack the cysteine. Leveraging the covalent ligandability of C109 in the cyclin CCNE2, we mutated the corresponding residue in paralog CCNE1 to cysteine (N112C) and found through activity-based protein profiling (ABPP) that this mutant reacts stereoselectively and site-specifically with tryptoline acrylamides. We then converted the tryptoline acrylamide-N112C-CCNE1 interaction into a NanoBRET-ABPP assay capable of identifying compounds that reversibly inhibit both N112C- and WT-CCNE1:CDK2 complexes. X-ray crystallography revealed a cryptic allosteric pocket at the CCNE1:CDK2 interface adjacent to N112 that binds the reversible inhibitors. Our findings thus provide a roadmap for leveraging electrophile-cysteine interactions to extend the ligandability of the proteome beyond covalent chemistry.
HostingRepository	PRIDE
AnnounceDate	2024-09-03
AnnouncementXML	Submission_2024-09-03_13:15:51.038.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yuanjin Zhang
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-13 06:30:45	ID requested
⏵ 1	2024-09-03 13:15:57	announced

Zhang Y, Liu Z, Hirschi M, Brodsky O, Johnson E, Won SJ, Nagata A, Petroski MD, Majmudar JD, Niessen S, VanArsdale T, Gilbert AM, Hayward MM, Stewart AE, Nager AR, Melillo B, Cravatt B, Expanding the ligandable proteome by paralog hopping with covalent probes. bioRxiv, ():(2024) [pubmed]

10.1101/2024.01.18.576274;

submitter keyword: Proteomics, Chemical Biology

Benjamin Cravatt
contact affiliation	Department of Chemistry Scripps Research
contact email	cravatt@scripps.edu
lab head
Yuanjin Zhang
contact affiliation	Scripps Research
contact email	yuzhang@scripps.edu
dataset submitter

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/2024/09/PXD053077

PRIDE project URI

• PRIDE
  1. PXD053077
     1. Label: PRIDE project
     2. Name: Protein-directed ABPP describing proteome-wide reactivities of WX-02-520 and WX-02-521 probes