PXD043794 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | A PARP2 active site α-helix melts to permit DNA damage-induced enzymatic activation |
Description | PARP1 and PARP2 recognize DNA breaks immediately upon their formation, generate a burst of local PARylation to signal their location, and are co-targeted by all current FDA-approved forms of PARP inhibitors (PARPi) used in the cancer clinic. Recent evidence indicates that the same PARPi molecules impact PARP2 differently from PARP1, raising the possibility that allosteric activation may also differ. We find that unlike for PARP1, destabilization of the autoinhibitory domain of PARP2 is insufficient for DNA damage-induced catalytic activation. Rather, PARP2 activation requires further unfolding of an active site α-helix. In contrast, the corresponding α-helix in PARP1 only transiently forms, even prior to engaging DNA. Only one clinical PARPi, Olaparib, stabilizes the PARP2 active site α-helix, representing a structural feature with the potential to discriminate small molecule inhibitors. Collectively, our findings reveal unanticipated differences in local structure and changes in activation-coupled backbone dynamics between PARP1 and PARP2. |
HostingRepository | PRIDE |
AnnounceDate | 2024-10-22 |
AnnouncementXML | Submission_2024-10-22_07:00:04.414.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Emily Smith |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | No PTMs are included in the dataset |
Instrument | Q Exactive HF |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2023-07-14 12:36:42 | ID requested | |
1 | 2024-09-30 06:06:35 | announced | |
⏵ 2 | 2024-10-22 07:00:04 | announced | 2024-10-22: Updated project metadata. |
Publication List
Keyword List
submitter keyword: PARP2, PARPi, HDX-MS, active site loop |
Contact List
Dr. Ben |
contact affiliation | University of Pennsylvania, Biochemistry & Biophysics, Philadelphia, PA, 19104, USA |
contact email | blackbe@pennmedicine.upenn.edu |
lab head | |
Emily Smith |
contact affiliation | University of Pennsylvania |
contact email | espillet@pennmedicine.upenn.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/2024/09/PXD043794 |
PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD043794
- Label: PRIDE project
- Name: A PARP2 active site α-helix melts to permit DNA damage-induced enzymatic activation