PXD051134
PXD051134 is an original dataset announced via ProteomeXchange.
Dataset Summary
Title | Therapeutic potential of allosteric HECT E3 ligase inhibition |
Description | Supplemental proteomics data Abstract: Inhibition of ubiquitin E3-ligases is therapeutically attractive; however, the absence of an active-site pocket impedes computational approaches to inhibitor identification. In a large unbiased physical screen, we discovered inhibitors that bind a cryptic cavity distant from the protruding SMURF1 catalytic cysteine. Structural and biochemical analyses, and engineered escape mutants, revealed that the inhibitors restrict an essential catalytic motion by extending an α-helix over a conserved glycine-hinge. SMURF1 is overexpressed in patients with pulmonary arterial hypertension (PAH), a disease caused by mutation of bone morphogenetic protein receptor-2 (BMPR2). We demonstrated that SMURF1 inhibition prevents direct BMPR2 ubiquitylation, normalizes BMP-signaling, restores pulmonary vascular cell homeostasis and reverses pathology in established, experimental PAH. We leveraged this deep mechanistic understanding to undertake a machine learning-based screen that identified inhibitors of the prototypic HECT E6AP, and confirm glycine-hinge-dependent allosteric activity. Inhibition of HECT E3s and other glycine-hinge proteins opens a new druggable space. |
HostingRepository | PRIDE |
AnnounceDate | 2025-05-26 |
AnnouncementXML | Submission_2025-05-25_16:18:51.783.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Tomas Rejtar |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | iodoacetamide derivatized residue |
Instrument | Orbitrap Fusion Lumos |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
---|---|---|---|
0 | 2024-04-01 15:32:55 | ID requested | |
⏵ 1 | 2025-05-25 16:18:52 | announced |
Publication List
Rothman AMK, Florentin A, Zink F, Quigley C, Bonneau O, Hemmig R, Hachey A, Rejtar T, Thaker M, Jain R, Huang SM, Sutton D, Roger J, Zhang JH, Weiler S, Cotesta S, Ottl J, Srivastava S, Kordonsky A, Avishid R, Yariv E, Rathi R, Khvalevsky O, Troxler T, Binmahfooz SK, Kleifeld O, Morrell NW, Humbert M, Thomas MJ, Jarai G, Beckwith REJ, Cobb JS, Smith N, Ostermann N, Tallarico J, Shaw D, Guth-Gundel S, Prag G, Rowlands DJ, Therapeutic potential of allosteric HECT E3 ligase inhibition. Cell, 188(10):2603-2620.e18(2025) [pubmed] |
10.1016/j.cell.2025.03.001; |
Keyword List
submitter keyword: drug discovery, E6AP, pulmonary arterial hypertension, small molecule,Ubiquitin E3-ligase, vascular remodeling, HECT, allosteric inhibition, SMURF1, glycine hinge |
Contact List
Tomas Rejtar | |
---|---|
contact affiliation | Novartis Biomedical Research, Cambridge, MA, USA |
contact email | tomas.rejtar@novartis.com |
lab head | |
Tomas Rejtar | |
contact affiliation | Novartis Institutes for Biomedial Research |
contact email | tomas.rejtar@novartis.com |
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/2025/05/PXD051134 |
PRIDE project URI |
Repository Record List
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