PXD051134

PXD051134 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2024-04-01 15:32:55	ID requested
⏵ 1	2025-05-25 16:18:52	announced

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;

submitter keyword: drug discovery, E6AP, pulmonary arterial hypertension, small molecule,Ubiquitin E3-ligase, vascular remodeling, HECT, allosteric inhibition, SMURF1, glycine hinge

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

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

• PRIDE
  1. PXD051134
     1. Label: PRIDE project
     2. Name: Therapeutic potential of allosteric HECT E3 ligase inhibition