PXD082934

PXD082934 is an original dataset announced via ProteomeXchange.

Title	Activity-based profiling of primary brain cells identifies covalent allosteric modulators of HCN channels
Description	Chemical proteomics can provide global portraits of small molecule-protein interactions in native biological systems. However, such ligandability maps have, to date, mostly been restricted to readily accessible cancer cell lines or primary immune cells. Here, we describe an activity-based protein profiling (ABPP) strategy for mapping the covalent ligandability of primary brain cells freshly isolated from mice. By investigating sets of stereochemically defined electrophilic small molecules ("stereoprobes"), we identify liganding events for diverse proteins, including many with nervous system-enriched expression profiles. In this category were multiple hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which we show are covalently liganded by tryptoline acrylamide stereoprobes at a conserved cysteine in their cyclic nucleotide-binding domain. The stereoprobes were found to block cAMP-dependent shifts in voltage dependence while sparing basal HCN channel activity. Our work describes an advanced ABPP platform for identifying ligands targeting nervous system-enriched proteins, including chemical probes for modulating HCN channel function in cells.
HostingRepository	PRIDE
AnnounceDate	2026-08-26
AnnouncementXML	Submission_2026-08-26_08:51:56.405.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Elva Ye
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606; scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2026-08-20 20:59:29	ID requested
⏵ 1	2026-08-26 08:51:57	announced

10.64898/2026.08.25.747126;

submitter keyword: covalent ligandability, tryptoline acrylamide, cyclic nucleotide signaling, chemical proteomics, ligand discovery, HCN channels,Activity-based protein profiling, primary brain cells

Benjamin Cravatt
contact affiliation	Department of Chemistry, Scripps Research
contact email	cravatt@scripps.edu
lab head
Elva Ye
contact affiliation	Scripps Research
contact email	eye@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/2026/08/PXD082934

PRIDE project URI

• PRIDE
  1. PXD082934
     1. Label: PRIDE project
     2. Name: Activity-based profiling of primary brain cells identifies covalent allosteric modulators of HCN channels