PXD031384-2

PXD031384 is an original dataset announced via ProteomeXchange.

Title	Selective inhibitors of JAK1 targeting a subtype-restricted allosteric cysteine
Description	The JAK family of non-receptor tyrosine kinases includes four subtypes (JAK1, JAK2, JAK3, and TYK2) and is responsible for signal transduction downstream of diverse cytokine receptors. JAK inhibitors have emerged as important therapies for immuno(onc)ological disorders, but their use is limited by undesirable side effects presumed to arise from poor subtype selectivity, a common challenge for inhibitors targeting the ATP-binding pocket of kinases. Here, we describe the chemical proteomic discovery of a druggable allosteric cysteine present in the non-catalytic pseudokinase domain of JAK1 (C817) and TYK2 (C838), but absent from JAK2 or JAK3. Electrophilic compounds selectively engaging this site block JAK1-dependent transphosphorylation and cytokine signaling, while appearing to act largely as “silent” ligands for TYK2. Importantly, the allosteric JAK1 inhibitors do not impair JAK2-dependent cytokine signaling and are inactive in cells expressing a C817A JAK1 mutant. Our findings thus reveal an allosteric approach for inhibiting JAK1 with unprecedented subtype selectivity.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_09:02:48.364.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Madeline Kavanagh
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2022-02-01 04:51:47	ID requested
1	2023-07-20 10:56:16	announced
⏵ 2	2023-11-14 09:02:49	announced	2023-11-14: Updated project metadata.

Kavanagh ME, Horning BD, Khattri R, Roy N, Lu JP, Whitby LR, Ye E, Brannon JC, Parker A, Chick JM, Eissler CL, Wong AJ, Rodriguez JL, Rodiles S, Masuda K, Teijaro JR, Simon GM, Patricelli MP, Cravatt BF, Selective inhibitors of JAK1 targeting an isoform-restricted allosteric cysteine. Nat Chem Biol, 18(12):1388-1398(2022) [pubmed]

submitter keyword: ABPP, PBMC, cysteine,allosteric, splenocyte, kinase, JAK1 inhibitor

Benjamin F. Cravatt
contact affiliation	Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA
contact email	cravatt@scripps.edu
lab head
Madeline Kavanagh
contact affiliation	The Scripps Research Institute
contact email	mkavanagh@scripps.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/2023/07/PXD031384

PRIDE project URI

• PRIDE
  1. PXD031384
     1. Label: PRIDE project
     2. Name: Selective inhibitors of JAK1 targeting a subtype-restricted allosteric cysteine