PXD016188

PXD016188 is an original dataset announced via ProteomeXchange.

Title	The CDK12-inhibitor CR8 mediates Cyclin K degradation through the CUL4-RBX1-DDB1 E3 ubiquitin ligase
Description	Small molecules have been identified that induce protein-protein interactions between a substrate and a ubiquitin ligase, resulting in targeted protein degradation. Such molecular glue compounds, unlike traditional enzyme inhibitors, act sub-stoichiometrically to catalyse rapid depletion of previously inaccessible targets. Molecular glue degraders have the potential for clinical efficacy, but have thus far only been discovered serendipitously. Through correlations between compound cytotoxicity and E3 ligase expression levels, we found that CR8, a cyclin-dependent kinase (CDK) inhibitor, acts as a molecular glue degrader. A surface-exposed pyridyl moiety of CR8 is sufficient to induce complex formation between CDK12-Cyclin K and DDB1, a component of CUL4 E3 ubiquitin ligase complexes, which presents Cyclin K for ubiquitination and degradation. Our results reveal that minor surface-exposed modifications confer gain-of-function glue properties to an inhibitor. We hypothesize that chemical alteration of surface-exposed moieties is a broad strategy to turn a target binder into a molecular glue.
HostingRepository	PRIDE
AnnounceDate	2020-06-10
AnnouncementXML	Submission_2020-06-09_23:26:45.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eric Fischer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-11-07 02:11:18	ID requested
⏵ 1	2020-06-09 23:26:46	announced

S, ł, abicki M, Kozicka Z, Petzold G, Li YD, Manojkumar M, Bunker RD, Donovan KA, Sievers QL, Koeppel J, Suchyta D, Sperling AS, Fink EC, Gasser JA, Wang LR, Corsello SM, Sellar RS, Jan M, Gillingham D, Scholl C, Fr, ö, hling S, Golub TR, Fischer ES, Thom, ä NH, Ebert BL, The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. Nature, 585(7824):293-297(2020) [pubmed]

submitter keyword: CDK12, cyclin k, CRL4DDB1, molecular glue, CR8, ubiquitin

Eric Fischer
contact affiliation	Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
contact email	eric_fischer@dfci.harvard.edu
lab head
Eric Fischer
contact affiliation	Dana-Farber Cancer Institute
contact email	eric_fischer@dfci.harvard.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/2020/06/PXD016188

PRIDE project URI

• PRIDE
  1. PXD016188
     1. Label: PRIDE project
     2. Name: The CDK12-inhibitor CR8 mediates Cyclin K degradation through the CUL4-RBX1-DDB1 E3 ubiquitin ligase