PXD074619

PXD074619 is an original dataset announced via ProteomeXchange.

Title	A Global Ligandability Map of Tryptoline Butynamide Stereoprobes Identifies Covalent Inhibitors of the Actin Maturation Protease ACTMAP
Description	Covalent chemistry coupled with activity-based protein profiling (ABPP) offers a versatile approach for small-molecule ligand discovery in native biological contexts. The covalent ligandability maps generated by ABPP that target cysteine have frequently leveraged the acrylamide as a reactive group due to its tempered electrophilicity and presence in many advanced tool compounds and therapeutics. More recently, alternative cysteine-directed re-active groups such as the butynamide have emerged as an additional source of covalent probes and drugs, but their global reactivity with the proteome remains largely unexplored. Here, we compare the ligandability maps of stereochemically defined acrylamide and bu-tynamide compounds (stereoprobes) built from a common tryptoline core and find that the butynamides, despite exhibiting attenuated intrinsic and proteome-wide reactivity, prefer-entially engage a diverse set of proteins in human cancer cells. Among the butynamide-preferring proteins was C19orf54/ACTMAP, a cysteine protease required for the post-translational maturation of actin. We show that (1S, 3R)-tryptoline butynamides stereose-lectively react with the catalytic nucleophile of ACTMAP, leading to accumulation of N-terminally unprocessed actin in cancer cells. Our findings support reactive group diversifi-cation as a strategy for expanding the ligandability of the human proteome and the bu-tynamide, more specifically, as a differentiated cysteine-directed electrophile for chemical probe discovery.
HostingRepository	PRIDE
AnnounceDate	2026-05-20
AnnouncementXML	Submission_2026-05-20_14:43:21.273.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yijun Xiong
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2026-02-18 22:15:54	ID requested
⏵ 1	2026-05-20 14:43:22	announced

Xiong Y, Reinhardt CJ, Nguyen T, Hoffman MA, Simon GM, Melillo B, Cravatt BF, A Global Ligandability Map of Tryptoline Butynamide Stereoprobes Identifies Covalent Inhibitors of the Actin Maturation Protease. J Am Chem Soc, 148(21):22077-22090(2026) [pubmed]

10.1021/jacs.6c03985;

submitter keyword: None

Benjamin Cravatt
contact affiliation	Scripps Research
contact email	cravatt@scripps.edu
lab head
Yijun Xiong
contact affiliation	Scripps Research
contact email	yxiong@scripps.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD074619
     1. Label: PRIDE project
     2. Name: A Global Ligandability Map of Tryptoline Butynamide Stereoprobes Identifies Covalent Inhibitors of the Actin Maturation Protease ACTMAP