PXD051581

PXD051581 is an original dataset announced via ProteomeXchange.

Title	Principles of isoform-specific targeted protein degradation engaging the C-degron E3 KLHDC2
Description	Targeted protein degradation (TPD) via molecular glues or PROTACs (Proteolysis-targeting chimeras) is an up-and-coming drug modality holding promise to drug the “undrugabbles.” Further expanding the collection of targetable E3 ligases for TPD, we report the discovery of ligands targeting the C-END degron receptor KLHDC2. Utilizing the BRD targeting ligand JQ1 as a test case, we demonstrate that KLHDC2 ligands can be readably converted to PROTACs for TPD, enabling remarkable isoform selectivity and cooperative ternary complex formation with BRD3BD2. We demonstrate that formation of cooperative neo-substrate ternary complexes with KLHDC2 is largely reliant on the exit vector emanating from the ligand bound deep in KLHDC2s U-shaped di-Gly binding pocket. Additionally, we establish the feasibility of generating selective ligands targeting KLHDC2, as the ligands developed here are unable to target the related binding pockets of the KLH family members KLHDC1, KLHDC3, or KLHDC10. Finally, we establish that KLHDC2 targeting ligands can effortlessly overcome the degron-mimic mediated tetramerization and inhibition of KLHDC2-EloB/C and that pro-drug variants can overt cellular permeability limitations of small molecules retaining acid binding moieties. In sum, our study confirms prior observations suggesting KLHDC2 might be amendable to TPD and establish principles to guide PROTAC development targeting C-END E3 ligases.
HostingRepository	PRIDE
AnnounceDate	2025-01-18
AnnouncementXML	Submission_2025-01-17_19:53:06.659.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Joao Paulo
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-04-19 08:20:00	ID requested
⏵ 1	2025-01-17 19:53:07	announced

10.1038/s41467-024-52966-3;

Scott DC, Dharuman S, Griffith E, Chai SC, Ronnebaum J, King MT, Tangallapally R, Lee C, Gee CT, Yang L, Li Y, Loudon VC, Lee HW, Ochoada J, Miller DJ, Jayasinghe T, Paulo JA, Elledge SJ, Harper JW, Chen T, Lee RE, Schulman BA, Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2. Nat Commun, 15(1):8829(2024) [pubmed]

submitter keyword: ProTAC, TPD, ubiquitin, BRD3, KLHDC2

Brenda A. Schulman
contact affiliation	Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany
contact email	schulman@biochem.mpg.de
lab head
Joao Paulo
contact affiliation	Harvard Medical School
contact email	joao_paulo@post.harvard.edu
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/2025/01/PXD051581

PRIDE project URI

• PRIDE
  1. PXD051581
     1. Label: PRIDE project
     2. Name: Principles of isoform-specific targeted protein degradation engaging the C-degron E3 KLHDC2