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News & Views |
Handling a protein with a nanopore machine
A protein–nanopore machine that can unfold, thread and degrade a protein has now been developed. Fabricated in a bottom-up fashion, the nanopore machine is assembled from three proteins and provides an important step towards deciphering the sequence of single proteins via nanopores.
- Yi-Lun Ying
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Article |
Wittig reagents for chemoselective sulfenic acid ligation enables global site stoichiometry analysis and redox-controlled mitochondrial targeting
Triphenylphosphonium ylides (Wittig reagents) that selectively react with sulfenic acids—a pivotal post-translational cysteine modification in redox biology—are developed. This bioconjugation method enables a site-specific proteome-wide stoichiometry analysis of S-sulfenylation, and visualization of redox-dependent changes in mitochondrial cysteine oxidation and the redox-triggered generation of triphenylphosphonium for the controlled delivery of small molecules to mitochondria.
- Yunlong Shi
- , Ling Fu
- & Kate S. Carroll
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Article |
A proteome-wide atlas of lysine-reactive chemistry
A deep chemical proteomic investigation of diverse aminophilic electrophiles has identified ligandable lysines across a wide range of human proteins. The proteins cover different functional and structural classes, and the aminophilic electrophiles include compounds that disrupt protein–protein and protein–RNA interactions. This dataset provides a proteome-wide atlas of lysine-reactive chemistry.
- Mikail E. Abbasov
- , Madeline E. Kavanagh
- & Benjamin F. Cravatt
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Article
| Open AccessChemical profiling of DNA G-quadruplex-interacting proteins in live cells
DNA–protein interactions are essential to genome function, but they are challenging to map in a cellular environment. Now, a chemical proteomics approach, which uses DNA G-quadruplex-specific ligands containing a photocrosslinking motif, has enabled the systematic identification of DNA G-quadruplex-binding proteins in live cells.
- Xiaoyun Zhang
- , Jochen Spiegel
- & Shankar Balasubramanian
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Article |
Using sulfuramidimidoyl fluorides that undergo sulfur(vi) fluoride exchange for inverse drug discovery
Latent functional groups—typically unreactive unless activated by protein binding—can provide additional selectivity to covalent drugs. Now, compounds containing the weakly electrophilic sulfuramidimidoyl fluoride group, capable of undergoing sulfur(vi) fluoride exchange, have been used to identify reactive proteins in human cell lysate. This approach has identified a compound that conjugates to and inhibits an important anticancer target.
- Gabriel J. Brighty
- , Rachel C. Botham
- & Jeffery W. Kelly
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Article |
In situ chromatin interactomics using a chemical bait and trap approach
Proteins that interact with histone post-translational modifications have now been identified using an approach based on split-intein mediated histone semisynthesis. Histone modifications and disease-relevant mutations were installed into native chromatin with an adjacent photocross-linker to enable in situ cross-linking. This strategy enabled the determination of chromatin-relevant interactomes and represents a powerful tool for exploring epigenetic regulation and dysregulation at the molecular level.
- Antony J. Burton
- , Michael Haugbro
- & Tom W. Muir
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News & Views |
A chiral trick to map protein ligandability
Biological receptors distinguish between S- and R-enantiomers and these subtle differences in chirality can lead to vastly different protein affinities. Now, a proteomics approach has been developed that capitalizes on chirality to map enantiomeric probe pairs and provides a rapid and global view of protein ligandability within the cell.
- Yuka Amako
- & Christina M. Woo
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Article |
Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs
A set of enantioprobes—photoreactive, clickable fragment pairs differing only in absolute stereochemistry—have been used to provide a robust and streamlined chemical proteomic map of small-molecule/protein interactions in human cells. More than 170 stereoselective fragment–protein interactions were discovered and shown to occur at functional sites on proteins from diverse classes.
- Yujia Wang
- , Melissa M. Dix
- & Benjamin F. Cravatt
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Article |
Dual chemical probes enable quantitative system-wide analysis of protein prenylation and prenylation dynamics
Two chemical probes, YnF and YnGG, that enable the identification of prenylated peptides and global analysis of protein prenylation using quantitative chemical proteomics have now been developed. Prenylation dynamics in response to pharmacological inhibition of prenyl-transferase enzymes were also studied. As a final demonstration, defective Rab prenylation in a model of the retinal degenerative disease choroideremia was also quantified.
- Elisabeth M. Storck
- , Julia Morales-Sanfrutos
- & Edward W. Tate
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Article |
Mining the cellular inventory of pyridoxal phosphate-dependent enzymes with functionalized cofactor mimics
A chemical proteomic strategy has now been developed for profiling pyridoxal-phosphate dependent enzymes (PLP-DEs) in cells. Pyridoxal-based probes are phosphorylated in situ and bind to cellular PLP-DEs as cofactor mimics. The method accessed 73% of the Staphylococcus aureus PLP-dependent proteome and annotated uncharacterized proteins as novel PLP-DEs.
- Annabelle Hoegl
- , Matthew B. Nodwell
- & Stephan A. Sieber
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Article |
Global profiling of lysine reactivity and ligandability in the human proteome
A chemical proteomic strategy has now been reported for the global profiling of lysine reactivity and ligandability. Using this approach, >9000 lysines in the human proteome were evaluated, leading to the discovery of hyper-reactive lysines, and lysines that can be targeted by electrophilic small molecules to perturb enzyme function and protein–protein interactions.
- Stephan M. Hacker
- , Keriann M. Backus
- & Benjamin F. Cravatt
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Article |
Chemoproteomic profiling and discovery of protein electrophiles in human cells
A chemical proteomic strategy is described for the discovery of protein-bound electrophilic groups in human cells. Using this approach, the dynamic regulation of the pyruvoyl catalytic cofactor in S-adenosyl-L-methionine decarboxylase was characterized and an N-terminal glyoxylyl modification on secernin proteins was discovered.
- Megan L. Matthews
- , Lin He
- & Benjamin F. Cravatt
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News & Views |
Knockout for malaria
Discovering and validating new targets is urgently required to tackle the rise in resistance to antimalarial drugs. Now, inhibition of the enzyme N-myristoyltransferase has been shown to prevent the formation of a critical subcellular organelle in the parasite that causes malaria, leading to death of the parasite.
- Joanna Krysiak
- & Stephan A. Sieber
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Article |
Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach
Chemical validation of new drug targets is urgently required to help develop new antimalarial therapies. Here, chemical proteomic tools and selective enzyme inhibitors are combined to study protein lipidation in human malaria parasites, leading to in vitro and in vivo validation of the enzyme N-myristoyltransferase as a drug target.
- Megan H. Wright
- , Barbara Clough
- & Edward W. Tate
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News & Views |
Whispering within
Dynamic communication between atoms within folded proteins is potentially important for function, but its measurement has been a challenge. Now, a combined NMR and modelling study provides insights on the presence and strengths of such correlations.
- Rafael Brüschweiler
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News & Views |
Rewiring nanostructures
The cell's dynamic skeleton, a tightly regulated network of protein fibres, continues to provide inspiration for the design of synthetic nanostructures. Genetic engineering has now been used to encode non-biological functionality within these structures.
- Rein V. Ulijn
- & Pier-Francesco Caponi
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Research Highlights |
Sticky situation
The sliding movement of the actin–myosin protein conjugate responsible for contracting muscles can be inhibited using a dendrimer that glues them together.
- Gavin Armstrong