PXD053077 is an
original dataset announced via ProteomeXchange.
Dataset Summary
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 |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2024-06-13 06:30:45 | ID requested | |
⏵ 1 | 2024-09-03 13:15:57 | announced | |
Publication List
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; |
Keyword List
submitter keyword: Proteomics, Chemical Biology |
Contact List
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 | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD053077
- Label: PRIDE project
- Name: Protein-directed ABPP describing proteome-wide reactivities of WX-02-520 and WX-02-521 probes