PXD041314-1

PXD041314 is an original dataset announced via ProteomeXchange.

Title	Assigning functionality to cysteines by base editing of cancer dependency genes
Description	Covalent chemistry represents an attractive strategy for expanding the ligandability of the proteome, and chemical proteomics has revealed numerous electrophile-reactive cysteines on diverse human proteins. Determining which of these covalent binding events impact protein function, however, remains challenging. Here, we describe a base-editing strategy to infer the functionality of cysteines by quantifying the impact of their missense mutation on cancer cell proliferation. The resulting atlas, which covers >13,800 cysteines on >1,750 cancer dependency proteins, confirms the essentiality of cysteines targeted by covalent drugs and, when integrated with chemical proteomic data, identifies essential, ligandable cysteines in >110 cancer dependency proteins. We further show that a stereoselective and site-specific ligand targeting an essential cysteine in TOE1 inhibits the nuclease activity of this protein through an apparent allosteric mechanism. Our findings thus describe a versatile method and valuable resource to prioritize the pursuit of small-molecule probes with high function-perturbing potential.
HostingRepository	PRIDE
AnnounceDate	2023-09-06
AnnouncementXML	Submission_2023-09-06_09:41:46.910.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	HaoxinLi
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-04-03 14:48:10	ID requested
⏵ 1	2023-09-06 09:41:47	announced
2	2023-11-14 07:51:30	announced	2023-11-14: Updated project metadata.

submitter keyword: ABPP, cysteine, base editing,covalent probe

BenjaminCravatt
contact affiliation	The Scripps Research Institute
contact email	cravatt@scripps.edu
lab head
HaoxinLi
contact affiliation	The Scripps Research Institute
contact email	haoxinli@scripps.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD041314
     1. Label: PRIDE project
     2. Name: Assigning functionality to cysteines by base editing of cancer dependency genes