PXD035111 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Validation and application of a novel KLK6 activity based probe (IMP2352) |
Description | Pancreatic cancer has the lowest survival rate of all common cancers due to late diagnosis and limited treatment options. Serine hydrolases are known to mediate cancer progression and metastasis through initiation of signaling cascades and cleavage of extracellular matrix proteins, and the kallikrein-related peptidase (KLK) family of secreted serine proteases have emerging roles in pancreatic ductal adenocarcinoma (PDAC). However, the lack of reliable activity-based probes (ABP) to profile KLK activity has hindered progress in validation of these enzymes as potential targets or biomarkers. Here, we developed potent and selective ABPs for KLK6 by using a positional scanning combinatorial substrate library and characterized their binding mode and interactions by X-ray crystallography. The optimized KLK6 probe IMP-2352 (kobs/I = 11,000 M-1 s-1) enabled selective detection of KLK6 activity in a variety of PDAC cell lines, and we observed that KLK6 inhibition reduced the invasiveness of PDAC cells that secrete active KLK6. KLK6 inhibitors were combined with N-terminomics to identify potential secreted protein substrates of KLK6 in PDAC cells, providing insights into KLK6-mediated invasion pathways. These novel KLK6 ABPs offer a new toolset to validate KLK6 and associated signaling partners as targets or biomarkers across a range of diseases. |
HostingRepository | PRIDE |
AnnounceDate | 2023-11-14 |
AnnouncementXML | Submission_2023-11-14_07:46:30.541.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Leran Zhang |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | dimethylated residue |
Instrument | Q Exactive |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2022-07-06 14:20:39 | ID requested | |
1 | 2023-03-10 13:10:51 | announced | |
⏵ 2 | 2023-11-14 07:46:35 | announced | 2023-11-14: Updated project metadata. |
Publication List
Zhang L, Lovell S, De Vita E, Jagtap PKA, Lucy D, Goya Grocin A, Kj, æ, r S, Borg A, Hennig J, Miller AK, Tate EW, A KLK6 Activity-Based Probe Reveals a Role for KLK6 Activity in Pancreatic Cancer Cell Invasion. J Am Chem Soc, 144(49):22493-22504(2022) [pubmed] |
Keyword List
submitter keyword: ABPP, KLK ,activity-based probe, kallikrein-related peptidase, N-terminomics |
Contact List
Edward W Tate |
contact affiliation | Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London W12 0BZ, U.K. |
contact email | e.tate@imperial.ac.uk |
lab head | |
Leran Zhang |
contact affiliation | LGC |
contact email | lezhang@tcd.ie |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD035111
- Label: PRIDE project
- Name: Validation and application of a novel KLK6 activity based probe (IMP2352)