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Article
Biochemistry & Molecular Biology
Narek Darabedian et al.
Summary: Creatine kinases (CKs) are involved in local ATP production during periods of high energy demand. However, the role of CKs in cancer and their potential as therapeutic targets remain unknown. In this study, we developed a selective covalent inhibitor called CKi, which specifically targets the active site cysteine of CKs. We found that CKi effectively depletes creatine phosphate and selectively induces toxicity in CK-dependent acute myeloid leukemia. Furthermore, we discovered an essential role for CKs in the regulation of proinflammatory cytokine production in macrophages.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Tin-Yan Koo et al.
Summary: NAIAs with superior cysteine reactivity were developed to effectively probe functional cysteines and image oxidized thiols. Mass spectrometry experiments showed the successful capture of new oxidized cysteines, as well as ligandable cysteines and proteins. Competitive activity-based protein profiling demonstrated the ability of NAIA to discover lead compounds targeting these cysteines and proteins.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Yue Liu et al.
Summary: Chemical proteomics is a powerful technology for studying uncharacterized proteins in the human proteome. A new protein-labeling strategy using nitrile oxide has been developed, which can efficiently react with target proteins. This method has shown excellent chemoselectivity and successfully characterized over 4000 cysteine residues, including KRAS G12C, demonstrating its complementary utility.
ACS CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Katharine E. Gilbert et al.
Summary: A comprehensive profiling of sulfur(VI) fluoride reactivity is presented, focusing on fragment binders and optimized probes. The reactivity profile of S-VI-Fs is demonstrated through live cell chemoproteomics. The studies provide insights into the hydrolytic stability, protein reactivity, and chemoproteomic utility of S-VI-Fs, offering a valuable guide for designing ligands containing S-VI-Fs and expanding the liganded proteome.
ACS CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Lisa M. Boatner et al.
Summary: CysDB is a curated community-wide repository of human cysteine chemoproteomics data derived from nine high-coverage studies. It provides measures of identification for 62,888 cysteines (24% of the cysteinome), as well as annotations of functionality, druggability, disease relevance, genetic variation, and structural features. CysDB is designed to incorporate new datasets and support the continued growth of the druggable cysteinome.
CELL CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Fan Yang et al.
Summary: Activity-based protein profiling (ABPP) is a powerful tool for annotating protein functions and discovering targets of bioactive ligands. In this study, we combined data-independent acquisition (DIA) MS with ABPP to develop a label-free quantitative chemical proteomic method called DIA-ABPP. With good reproducibility and high accuracy, DIA-ABPP allows for high-throughput quantification, enabling comprehensive profiling of functional proteomes and interactions with bioactive small molecules.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Nathaniel J. Henning et al.
Summary: This study describes a covalent ligand EN106 that targets FEM IB, an E3 ligase involved in the cellular response to reductive stress. EN106 disrupts the recognition of the reductive stress substrate FNIP1 by targeting C186 in FEM1B. Additionally, EN106 can serve as a covalent recruiter for FEM1B in targeted protein degradation (TPD) applications, leading to the degradation of BRD4 and BCR-ABL when linked to BET bromodomain inhibitor JQ1 or kinase inhibitor dasatinib, respectively.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Xie Wang et al.
Summary: Electrophilic cofactors play important roles in physiological and disease processes. This study develops a platform for analyzing the reactivity and selectivity of nucleophilic probes towards main-chain carbonyl cofactors, which can help in the development of selective inhibitors.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Biochemistry & Molecular Biology
Nathaniel J. Henning et al.
Summary: Many diseases caused by aberrant protein ubiquitination and degradation could benefit from targeted protein stabilization (TPS). In this study, deubiquitinase-targeting chimeras (DUBTACs) were used to stabilize specific proteins degraded in a ubiquitin-dependent manner, leading to therapeutic benefits. Covalent chemoproteomic approaches were used to identify a ligand, EN523, that targeted a specific deubiquitinase. DUBTACs consisting of EN523 and a protein-targeting ligand were shown to stabilize the levels of disease-related proteins, showing promise for TPS.
NATURE CHEMICAL BIOLOGY
(2022)
Article
Biochemical Research Methods
Esther K. Kemper et al.
Summary: Proteomics has revealed the vast diversity of proteins, or proteoforms, generated from around 20,000 human genes, largely due to post-translational modifications (PTMs). This study introduces a chemical proteomic method to quantitatively study the impact of serine/threonine phosphorylation on the reactivity of cysteine residues. The results show that phosphorylation can significantly affect the reactivity of cysteine residues, highlighting the potential for creating small-molecule probes that target proteoforms with PTMs.
Article
Biochemistry & Molecular Biology
Isabell Bludau et al.
Summary: The recent revolution in computational protein structure prediction has provided new insights into the study of the entire proteome. In this study, the researchers analyze posttranslational modifications (PTMs) of proteins to determine their structural context and investigate their potential regulatory sites. The analysis reveals global patterns of PTM occurrence and spatial coregulation of different types of PTMs.
Article
Biochemical Research Methods
Masaki Ishikawa et al.
Summary: In this study, an ultrafast proteomic method was established using a 5-min gradient LC and quadrupole-Orbitrap MS. By optimizing parameters, the method achieved a high throughput and sensitivity for measuring a large number of samples. The method was demonstrated to be applicable for chemical responsivity screening.
JOURNAL OF PROTEOME RESEARCH
(2022)
Article
Multidisciplinary Sciences
Hongyan Du et al.
Summary: Covalent ligands have unique advantages and developing computational methods to identify their binding sites is crucial. DeepCoSI is the first deep learning model for identifying ligandable covalent sites in proteins, and it demonstrates excellent predictive performance.
Article
Chemistry, Multidisciplinary
Yongfeng Tao et al.
Summary: This study reports the discovery of azetidine acrylamides that react stereoselectively and site-specifically with a cysteine in the E3 ligase substrate receptor DCAF1. These findings have the potential to develop electrophilic proteolysis-targeting chimeras (PROTACs) for targeted protein degradation and uncover ligandable sites on E3 ligases that support this process.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Biochemistry & Molecular Biology
Madeline E. Kavanagh et al.
Summary: This study identified a novel allosteric approach for selectively inhibiting JAK1 with unprecedented isoform selectivity, while acting as 'silent' ligands for TYK2.
NATURE CHEMICAL BIOLOGY
(2022)
Article
Microbiology
H. J. Benns et al.
Summary: This study developed a CRISPR-based CORe platform to identify and prioritize electrophile-sensitive cysteines in Toxoplasma gondii for drug discovery. It was found that electrophile-sensitive cysteines on the ribosome are critical for parasite growth, leading to the identification of a parasite-selective anti-malarial lead molecule.
NATURE MICROBIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Isabell Bludau et al.
Summary: The recent advancement in computational protein structure prediction allows integration with large-scale experimental data, helping to determine the structural context of posttranslational modifications (PTMs) and identify potential regulatory sites. Global patterns of PTM occurrence across folded and intrinsically disordered regions have been uncovered, with a focus on distinguishing regulatory PTMs from those marking improperly folded proteins in the human proteome.
Article
Biochemistry & Molecular Biology
Hongyan Du et al.
Summary: Covalent inhibitors, once considered highly adventurous, have seen increased attention in design and discovery due to clinical validation and approval in the past decade. The Covalent Inhibitor Database (CovalentInDB) presented in this study is the largest online resource providing structural information and experimental data for covalent inhibitors. With 4511 inhibitors for 280 protein targets, including 68 approved drugs, the database also offers crystal structures and experimental verification methods for each inhibitor. Users can download high-quality datasets for evaluating and developing computational methods for covalent drug design.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Chemistry, Analytical
Jian Cao et al.
Summary: This study optimized Suzuki-Miyaura cross-coupling conditions for activity-based protein profiling and mass-spectrometry-based chemoproteomics, allowing for target deconvolution and labeling site identification. By exploiting the observed orthogonality between palladium-catalyzed cross-coupling and CuAAC, dual labeling was achieved, and the protein targets of bifunctional probes were identified through multiplexed targeted deconvolution.
ANALYTICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Tianyang Yan et al.
Summary: Chemoproteomics has enabled rapid and proteome-wide discovery of functional cysteine residues using an optimized sample-preparation workflow and high-field asymmetric waveform ion mobility spectrometry (FAIMS) separation, achieving unprecedented coverage of >14000 unique cysteines in a single experiment. The method is also compatible with competitive small-molecule screening and has identified 34225 unique cysteines in 18 samples from seven cell lines using only approximately 28 hours of instrument time, providing a technical foundation for future studies on the human cysteineome.
Article
Chemistry, Medicinal
Elena De Vita
Summary: In the first decade of targeted covalent inhibition, scientists have made significant progress in reversing the previous trend that hindered the use of covalent inhibition in drug development, especially in the field of kinase inhibitors. The successful entry of KRAS(G12C) covalent inhibitors into clinical trials in 2019 has sparked great interest in the future potential of this area of drug discovery. Despite the achievements, there are still many unanswered questions and areas for improvement in terms of safety and effectiveness.
FUTURE MEDICINAL CHEMISTRY
(2021)
Article
Biotechnology & Applied Microbiology
Miljan Kuljanin et al.
Summary: This study presents a redesigned workflow called streamlined cysteine activity-based protein profiling (SLC-ABPP) for measuring amino acid side-chain reactivity, which significantly improves sample throughput. The method has been successfully applied to identify proteome-wide targets of various covalent inhibitors, while also creating a resource of cysteine reactivity data for further research.
NATURE BIOTECHNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Alex Bateman et al.
Summary: The UniProt Knowledgebase aims to provide users with a comprehensive, high-quality set of protein sequences annotated with functional information. Updates over the past two years have increased the number of sequences to approximately 190 million, with new methods to assess proteome completeness and quality. UniProtKB has responded to the COVID-19 pandemic by expertly curating relevant entries and making them rapidly available through a dedicated portal.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Chemistry, Multidisciplinary
Daniel Abegg et al.
Summary: The tetrafluoroalkyl benziodoxole (TFBX) has emerged as a powerful cysteine-selective chemoproteomic probe, featuring superior target occupancy, faster labeling kinetics, and broader proteomic coverage compared to traditional cysteine-reactive probes. This new probe has been demonstrated to successfully identify cellular targets of (-)-myrocin G, leading to the discovery of the first reported inhibitors of the biomedically important protein XRCC5. Additionally, this probe disrupts the interaction of XRCC5 with DNA, sensitizing cancer cells to chemotherapeutic agents and UV-light-induced DNA damage.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Biochemistry & Molecular Biology
Maria F. Palafox et al.
Summary: The integration of chemoproteomics data with computational methods for predicting genetic variant pathogenicity revealed enrichment of deleterious genetic variants in codons of highly reactive cysteines. This study provides a roadmap for more precise inter-database mapping and highlights untapped opportunities to improve the predictive power of pathogenicity scores and prioritize putative druggable sites.
MOLECULAR SYSTEMS BIOLOGY
(2021)
Article
Biotechnology & Applied Microbiology
Christoph B. Messner et al.
Summary: The Scanning SWATH method accelerates mass spectrometric duty cycles to yield quantitative proteomes in combination with short gradients and high-flow chromatography, increasing precursor identifications by approximately 70% compared to conventional methods. This approach has been successfully demonstrated in drug mode-of-action screening and plasma proteomics studies, capturing the mode of action of specific drugs and identifying new biomarkers associated with COVID-19 severity. These results demonstrate significant acceleration and increased depth in fast proteomic experiments, facilitating proteomic drug screens and clinical studies.
NATURE BIOTECHNOLOGY
(2021)
Article
Multidisciplinary Sciences
John Jumper et al.
Summary: Proteins are essential for life, and accurate prediction of their structures is a crucial research problem. Current experimental methods are time-consuming, highlighting the need for accurate computational approaches to address the gap in structural coverage. Despite recent progress, existing methods fall short of atomic accuracy in protein structure prediction.
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