8C2G

14-3-3 sigma with Pin1 binding site pS72 and covalently bound CV1040

Summary for 8C2G

• Entry DOI: 10.2210/pdb8c2g/pdb
• Descriptor: 14-3-3 protein sigma, Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, 2-iodanyl-4-(2-phenylimidazol-1-yl)benzaldehyde, ... (5 entities in total)
• Functional Keywords: 14-3-3 sigma, pin1, covalent, stabilizer, peptide binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 29177.08

Authors

Verhoef, C.J.,Cossar, P. (deposition date: 2022-12-22, release date: 2023-06-14, Last modification date: 2024-11-06)

Primary citation

Verhoef, C.J.A.,Kay, D.F.,van Dijck, L.,Doveston, R.G.,Brunsveld, L.,Leney, A.C.,Cossar, P.J.
Tracking the mechanism of covalent molecular glue stabilization using native mass spectrometry.
Chem Sci, 14:6756-6762, 2023

PubMed Abstract: Molecular glues are powerful tools for the control of protein-protein interactions. Yet, the mechanisms underlying multi-component protein complex formation remain poorly understood. Native mass spectrometry (MS) detects multiple protein species simultaneously, providing an entry to elucidate these mechanisms. Here, for the first time, covalent molecular glue stabilization was kinetically investigated by combining native MS with biophysical and structural techniques. This approach elucidated the stoichiometry of a multi-component protein-ligand complex, the assembly order, and the contributions of covalent non-covalent binding events that govern molecular glue activity. Aldehyde-based molecular glue activity is initially regulated by cooperative non-covalent binding, followed by slow covalent ligation, further enhancing stabilization. This study provides a framework to investigate the mechanisms of covalent small molecule ligation and informs (covalent) molecular glue development.

PubMed: 37350830
DOI: 10.1039/d3sc01732j

Experimental method

X-RAY DIFFRACTION (1.6 Å)