PXD060708

PXD060708 is an original dataset announced via ProteomeXchange.

Title	O-Cyanobenzaldehydes (CNBA) Irreversibly Modify both Bur-ied and Exposed Lysine Residues in Live Cells
Description	Lysine residue represents an attractive site for covalent drug development due to high abundance (5.6%) and critical functions. However, very few lysines have been characterized to be accessible to covalent ligands and perturb the protein functions, owning to their protonation state and adjacent steric hindrance. Herein, we report a new lysine bioconjugation chemistry, O-Cyanobenzaldehydes (CNBA), that enables selective modification of the lysine ε-amine to form iso-indolinones under physiological conditions. Proteome profiling enabled the mapping of 85 endogenous kinases in live cells, highlighting its potential for modifying buried catalytic lysines within the kinome. Further protein crystallography and mass spectrometry confirmed that K271_ABL1 and K162_AURKA are covalently targetable sites in kinases. Leverag-ing a structure-based drug design (SBDD), we incorporated CNBA into the core structure of Nutlin-3 to irreversibly inhibit MDM2-p53 interaction by targeting an exposed lysine K94 on the surface of MDM2. Importantly, we have demonstrated the potential application of CNBA as a lysine-recognized bioconjugation agent for developing new Antibody-drug conju-gates (ADCs). The results collectively validate CNBA as a new selective and efficient modifying agent with broad applica-tions for both buried and exposed lysine residues in live cells.
HostingRepository	PRIDE
AnnounceDate	2025-03-27
AnnouncementXML	Submission_2025-03-26_19:02:27.885.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jiangnan Zheng
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2025-02-11 22:41:39	ID requested
⏵ 1	2025-03-26 19:02:28	announced

10.1021/JACS.4C18006;

submitter keyword: ABPP,chemical proteomics

Ruijun Tian
contact affiliation	Southern University of Science and Technology
contact email	tianrj@sustech.edu.cn
lab head
Jiangnan Zheng
contact affiliation	Southern University of Science and Technology
contact email	jiangnan.chemistry@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD060708
     1. Label: PRIDE project
     2. Name: O-Cyanobenzaldehydes (CNBA) Irreversibly Modify both Bur-ied and Exposed Lysine Residues in Live Cells