PXD076410-1

PXD076410 is an original dataset announced via ProteomeXchange.

Title	Covalent allosteric inhibition of AARS1 lactyltransferase
Description	Alanyl-tRNA synthetase 1 (AARS1) was recently identified as a lactyltransferase responsible for protein lactylation, a modification associated with epigenetic regulation and metabolic adaptation. AARS1 catalyzes lysine lactylation via an ATP- and lactate- dependent, but lactyl-CoA-independent mechanism. Here, we report compounds that inhibit AARS1 activity through an unconventional mechanism. Among them, XY353 covalently binds C184 of AARS1, inducing steric clashes with F175 and triggering structural rearrangements in the region that displace W176, a key residue for lactate binding. By means of a combination of ITC, SPR, MD, FP, enzymatic assays and structural analysis, we show that XY353 and its derivatives inhibit AARS1 by competing with lactate via the C184–F175–W176 relay, establishing a covalent allosteric mechanism of inhibition, which is further confirmed by our cellular data that XY353 derivatives XY353-1 reduces lactylation of the AARS1 substrate YAP and suppresses the proliferation of HGC-27 cells. Collectively, these findings define a covalent allosteric mechanism for AARS1 inhibition and provide the first chemical tools to explore its biological functions.
HostingRepository	PRIDE
AnnounceDate	2026-07-29
AnnouncementXML	Submission_2026-07-29_09:15:18.072.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Siying Liu
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2026-03-31 12:46:07	ID requested
⏵ 1	2026-07-29 09:15:18	announced
2	2026-07-29 18:20:07	announced	2026-07-30: Updated project metadata.
3	2026-07-29 18:20:44	announced	2026-07-30: Updated project metadata.

Dataset with its publication pending

submitter keyword: lactyltransferase, covalent ligand, AARS1

Jinrong Min
contact affiliation	Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, China
contact email	yunyuanhuang@ccnu.edu.cn
lab head
Siying Liu
contact affiliation	Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, China
contact email	1511395365@qq.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/2026/07/PXD076410

PRIDE project URI

• PRIDE
  1. PXD076410
     1. Label: PRIDE project
     2. Name: Covalent allosteric inhibition of AARS1 lactyltransferase