PXD072708

PXD072708 is an original dataset announced via ProteomeXchange.

Title	Structure-based discovery of a chemical probe targeting the Tudor domain of FMRP
Description	Fragile X mental retardation protein (FMRP) is an RNA-binding protein whose loss of function is associated with neurodevelopmental disorders, including fragile X syndrome and autism, and whose aberrant overexpression has been linked to immune-related cancers. Here, we report XY6-1, a potent and selective antagonist that targets the tandem Tudor domain (TTD) of FMRP, a methylated-histone reader. Structural and mutagenesis analyses reveal that subtle differences in the shape of the aromatic cage contribute to the selective binding of XY6-1 to FMRP. Multiple orthogonal target engagement assays further demonstrate that XY6-1 specifically binds FMRP in cells and disrupts the interaction between FMRP-TTD and histone H3K79me3, thereby attenuating the DNA damage response (DDR), as evidenced by reduced γH2A.X levels. Collectively, this first-in-class chemical probe XY6-1, along with its fluorescent (XY6-1–FITC) and biotinylated (XY6-1–Biotin) derivatives and the negative control compound XY6-2, constitutes a valuable toolkit for elucidating the underexplored biological functions of FMRP.
HostingRepository	PRIDE
AnnounceDate	2026-07-30
AnnouncementXML	Submission_2026-07-29_18:50:31.645.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	boyi Li
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2026-01-06 06:39:17	ID requested
⏵ 1	2026-07-29 18:50:32	announced

Dataset with its publication pending

submitter keyword: Tudor domain,FMRP, chemical probe

Yunyuan Huang
contact affiliation	Central China Normal University, School of life sciences
contact email	yunyuanhuang@ccnu.edu.cn
lab head
boyi Li
contact affiliation	central china normal university
contact email	lby52900@163.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD072708
     1. Label: PRIDE project
     2. Name: Structure-based discovery of a chemical probe targeting the Tudor domain of FMRP