9KS5

The crystal structure of ABL1 in complex with K-CNBA-1

This is a non-PDB format compatible entry.

Summary for 9KS5

• Entry DOI: 10.2210/pdb9ks5/pdb
• Descriptor: Tyrosine-protein kinase ABL1 (2 entities in total)
• Functional Keywords: abl1, k-cba-1, lysine modification, irreversible covalent probe, unknown function
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 64267.39

Authors

Zhang, Z.M.,Duan, L.P. (deposition date: 2024-11-29, release date: 2025-12-03, Last modification date: 2025-12-24)

Primary citation

Ling, H.,Li, L.,Duan, L.,Huang, W.,Zheng, J.,Zhang, S.,Li, X.,Qiu, X.,Zhou, Y.,Ma, N.,Ren, X.,Zhang, J.,Wang, Z.,Zhao, Y.,Tian, R.,Zhang, Z.M.,Ding, K.
O -Cyanobenzaldehydes Irreversibly Modify Both Buried and Exposed Lysine Residues in Live Cells.
J.Am.Chem.Soc., 147:11955-11963, 2025

PubMed Abstract: Lysine residue represents an attractive site for covalent drug development due to its 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, owing to their protonation state and adjacent steric hindrance. Herein, we report a new lysine bioconjugation chemistry, -cyanobenzaldehyde (CNBA), that enables selective modification of the lysine ε-amine to form iso-indolinones under physiological conditions. Activity-based proteome profiling enabled the mapping of 3451 lysine residues and 85 endogenous kinases in live cells, highlighting its potential for modifying hyper-reactive lysines within the proteome or 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. Leveraging a structure-based drug design, we incorporated CNBA into the core structure of Nutlin-3 to irreversibly inhibit the MDM2-p53 interaction by targeting an exposed lysine K94 on the surface of murine double minute 2. Importantly, we have demonstrated the potential application of CNBA as a lysine-recognized bioconjugation agent for developing new antibody-drug conjugates. The results collectively validate CNBA as a new selective and efficient modifying agent with broad applications for both buried and exposed lysine residues in live cells.

PubMed: 40150802
DOI: 10.1021/jacs.4c18006

Experimental method

X-RAY DIFFRACTION (2.2 Å)