Topic
DCPS
About: DCPS is a research topic. Over the lifetime, 144 publications have been published within this topic receiving 3121 citations.
Papers published on a yearly basis
Papers
TL;DR: Mutagenesis analysis revealed that the central histidine within the DCPS HIT motif is critical for decapping activity and defines the HIT motif as a new mRNA decapping domain, making DcpS the first member of the HIT family of proteins with a defined biological function.
Abstract: We recently demonstrated that the major decapping activity in mammalian cells involves DcpS, a scavenger pyrophosphatase that hydrolyzes the residual cap structure following 3′ to 5′ decay of an mRNA. The association of DcpS with 3′ to 5′ exonuclease exosome components suggests that these two activities are linked and there is a coupled exonucleolytic decay‐dependent decapping pathway. We purified DcpS from mammalian cells and identified the cDNA encoding a novel 40 kDa protein possessing DcpS activity. Consistent with purified DcpS, the recombinant protein specifically hydrolyzed methylated cap analog but did not hydrolyze unmethylated cap analog nor did it function on intact capped RNA. Sequence alignments of DcpS from different organisms revealed the presence of a conserved hexapeptide, containing a histidine triad (HIT) sequence with three histidines separated by hydrophobic residues. Mutagenesis analysis revealed that the central histidine within the DcpS HIT motif is critical for decapping activity and defines the HIT motif as a new mRNA decapping domain, making DcpS the first member of the HIT family of proteins with a defined biological function.
280 citations
TL;DR: By developing a strategy relying on the use of DNA clutch probes (DCPs) that render specific sequences of ctDNA accessible, the first detection of mutated ct DNA in samples collected from cancer patients without enzymatic amplification is reported.
Abstract: Progress toward the development of minimally invasive liquid biopsies of disease is being bolstered by breakthroughs in the analysis of circulating tumor DNA (ctDNA): DNA released from cancer cells into the bloodstream. However, robust, sensitive, and specific methods of detecting this emerging analyte are lacking. ctDNA analysis has unique challenges, since it is imperative to distinguish circulating DNA from normal cells vs mutation-bearing sequences originating from tumors. Here we report the electrochemical detection of mutated ctDNA in samples collected from cancer patients. By developing a strategy relying on the use of DNA clutch probes (DCPs) that render specific sequences of ctDNA accessible, we were able to readout the presence of mutated ctDNA. DCPs prevent reassociation of denatured DNA strands: they make one of the two strands of a dsDNA accessible for hybridization to a probe, and they also deactivate other closely related sequences in solution. DCPs ensure thereby that only mutated sequence...
190 citations
TL;DR: This work describes the first rational targeting of tyrosine residues in a protein binding site by small-molecule covalent probes, illustrating the utility of sulfonyl fluoride probes designed to react with specific tyrosines of a protein and augments the chemical biology toolkit by these probes uses in target validation and molecular pharmacology.
Abstract: This work describes the first rational targeting of tyrosine residues in a protein binding site by small-molecule covalent probes. Specific tyrosine residues in the active site of the mRNA-decapping scavenger enzyme DcpS were modified using reactive sulfonyl fluoride covalent inhibitors. Structure-based molecular design was used to create an alkyne-tagged probe bearing the sulfonyl fluoride warhead, thus enabling the efficient capture of the protein from a complex proteome. Use of the probe in competition experiments with a diaminoquinazoline DcpS inhibitor permitted the quantification of intracellular target occupancy. As a result, diaminoquinazoline upregulators of survival motor neuron protein that are used for the treatment of spinal muscular atrophy were confirmed as inhibitors of DcpS in human primary cells. This work illustrates the utility of sulfonyl fluoride probes designed to react with specific tyrosine residues of a protein and augments the chemical biology toolkit by these probes uses in tar...
170 citations
TL;DR: The B3LYP-DCP approach was tested on the S66, S22, and HSG-A benchmark sets of noncovalently interacting dimers and trimers and was found to significantly outperform almost all other DFT-based methods that were designed to treat van der Waals interactions.
Abstract: B3LYP is the most widely used density-functional theory (DFT) approach because it is capable of accurately predicting molecular structures and other properties. However, B3LYP is not able to reliably model systems in which noncovalent interactions are important. Here we present a method that corrects this deficiency in B3LYP by using dispersion-correcting potentials (DCPs). DCPs are utilized by simple modifications to input files and can be used in any computational package that can read effective-core potentials. Therefore, the technique requires no programming. DCPs (developed for H, C, N, and O) produce the best results when used in conjunction with 6-31+G(2d,2p) basis sets. The B3LYP-DCP approach was tested on the S66, S22, and HSG-A benchmark sets of noncovalently interacting dimers and trimers and was found to, on average, significantly outperform almost all other DFT-based methods that were designed to treat van der Waals interactions. Users of B3LYP who wish to model systems in which noncovalent interactions (viz., steric repulsion, hydrogen bonding, π-stacking) are present, should consider B3LYP-DCP.
165 citations
TL;DR: Using high-throughput chemical screening and genome-wide association analysis, 32 highly active compounds and genetic loci associated with differential chemical phenotypes (DCPs) are identified, defined as greater than or equal to fivefold differences in half-maximum inhibitor concentration (IC50) between parasite lines.
Abstract: Malaria remains a devastating disease largely because of widespread drug resistance. New drugs and a better understanding of the mechanisms of drug action and resistance are essential for fulfilling the promise of eradicating malaria. Using high-throughput chemical screening and genome-wide association analysis, we identified 32 highly active compounds and genetic loci associated with differential chemical phenotypes (DCPs), defined as greater than or equal to fivefold differences in half-maximum inhibitor concentration (IC(50)) between parasite lines. Chromosomal loci associated with 49 DCPs were confirmed by linkage analysis and tests of genetically modified parasites, including three genes that were linked to 96% of the DCPs. Drugs whose responses mapped to wild-type or mutant pfcrt alleles were tested in combination in vitro and in vivo, which yielded promising new leads for antimalarial treatments.
144 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2021 | 6 |
| 2020 | 5 |
| 2019 | 8 |
| 2018 | 6 |
| 2017 | 9 |
| 2016 | 6 |