PXD035924-1

PXD035924 is an original dataset announced via ProteomeXchange.

Title	Selective Macrocyclic Peptide Modulators of Lys63-linked Ubiquitin Chains Disrupt DNA Damage Repair
Description	Developing an effective binder for a specific ubiquitin (Ub) chain is a promising approach for modulating various biological processes with potential applications in drug discovery. In this study, we combined the Random Non-standard Peptides Integrated Discovery (RaPID) method and chemical protein synthesis to screen an extended library of macrocyclic peptides against synthetic Lys63-linked Di-Ub. This enabled us to discover a novel binder with low nanomolar affinity and specificity for this particular Ub chain. We further chemically modified the most effective binder to generate next-generation binders. We show that our potent cyclic peptide is cell-permeable and inhibits DNA damage repair, leading to cell cycle arrest and apoptotic cell death. Concordantly, a pulldown experiment with the biotinylated analog of our lead cyclic peptide identified various proteins involved in DNA synthesis and damage repair. Collectively, we established a novel and powerful strategy for selective inhibition of protein-protein interactions associated with Lys63-linked Di-Ub using cyclic peptides. This study offers an advancement in modulating central Ub pathways and provides new opportunities in drug discovery areas associated with Ub signaling.
HostingRepository	PRIDE
AnnounceDate	2022-09-19
AnnouncementXML	Submission_2022-09-18_23:33:09.126.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Keren Bendalak
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2022-08-10 08:02:08	ID requested
⏵ 1	2022-09-18 23:33:09	announced

Dataset with its publication pending

submitter keyword: Ubiquitin, DNA Damage Repair

Ashraf Brik
contact affiliation	Faculty of Biology, Technion - Israel institute of technology
contact email	abrik@technion.ac.il
lab head
Keren Bendalak
contact affiliation	Technion
contact email	kerenb@technion.ac.il
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD035924
     1. Label: PRIDE project
     2. Name: Selective Macrocyclic Peptide Modulators of Lys63-linked Ubiquitin Chains Disrupt DNA Damage Repair