Abstract
Intrinsically disordered proteins (IDPs) remain largely inaccessible to covalent chemical tools due to their structural plasticity and lack of defined pockets. We introduce a bioorthogonal cyclometalated gold(III) platform of monodentate phosphine-supported AuP1-8 complexes that selectively and irreversibly arylate cysteine residues via enhanced Lewis acidity. This platform enables targeting of low-reactivity, buried, or dynamically disordered cysteines across the human proteome. Chemoproteomic, structural, and computational analyses establish an expanded ligandable cysteinome, including transiently helical LLCLL motifs in intrinsically disordered regions (IDRs). Our findings establish a new class of metal-mediated bioorthogonal reagents for proteome-wide cysteine labeling, functional interrogation of disordered proteins, and future therapeutic and diagnostic applications.
| Original language | English |
|---|---|
| Journal | Angewandte Chemie - International Edition |
| DOIs | |
| State | Accepted/In press - 2025 |
Bibliographical note
Publisher Copyright:© 2025 Wiley-VCH GmbH.
Funding
This research was funded by the National Science Foundation's Chemistry of Life Processes program (Award CHE‐2203559) for S.G.A. D.D. was supported by NSF award CHE 2108134 to A.‐F.M. S.G.A is also supported by R01CA258421 from the National Cancer Institute. The authors used the MOE 2022.02 version for molecular docking studies, which was supported by NCI Cancer Center Support Grant (P30 CA177558). The authors gratefully acknowledge the support of various facilities at the University of Kentucky, including the UK NMR Center (NSF‐CHE‐997738) and the UK X‐ray facility (NSF‐CHE‐1625732). The authors also appreciate the assistance of Dr. Andrew Lemoff and the Proteomics Core facility at UT Southwestern for mass spectrometry and proteomics expertise. The authors acknowledge Awuah group members Chibuzor Olelewe and Oluwatosin Obisesan for experimental assistance. Thanks to Sashen Ruhunage for assistance in computational analysis.
| Funders | Funder number |
|---|---|
| Ministry of Education, Ethiopia | |
| National Science Foundation Arctic Social Science Program | R01CA258421, CHE 2108134, CHE‐2203559 |
| National Childhood Cancer Registry – National Cancer Institute | P30 CA177558 |
Keywords
- Bioorthogonal chemistry
- Covalent modification
- Cysteine arylation
- Gold(III) complexes
- Intrinsically disordered proteins (IDPs)
- Protein bioconjugation
- Proteomics
ASJC Scopus subject areas
- Catalysis
- General Chemistry