Abstract:
:Protein arginine N-methyltransferase 3 (PRMT3) belongs to the family of type I PRMTs and harbors the activity to use S-adenosyl-l-methionine (SAM) as a methyl-donor cofactor for protein arginine labeling. However, PRMT3's functions remain elusive with the lacked knowledge of its target scope in cellular settings. Inspired by the emerging Bioorthogonal Profiling of Protein Methylation (BPPM) using engineered methyltransferases and SAM analogues for target identification, the current work documents the endeavor to systematically explore the SAM-binding pocket of PRMT3 and identify suitable PRMT3 variants for BPPM. The M233G single point mutation transforms PRMT3 into a promiscuous alkyltransferase using sp(2)-β-sulfonium-containing SAM analogues as cofactor surrogates. Here the conserved methionine was defined as a hot spot that can be engineered alone or in combination with nearby residues to render cofactor promiscuity of multiple type I PRMTs. With this promiscuous variant and the matched 4-propargyloxy-but-2-enyl (Pob)-SAM analogue as the BPPM reagents, more than 80 novel proteins were readily uncovered as potential targets of PRMT3 in the cellular context. Subsequent target validation and functional analysis correlated the PRMT3 methylation to several biological processes such as cytoskeleton dynamics, whose roles might be compensated by other PRMTs. These BPPM-revealed substrates are primarily localized but not restricted in cytoplasm, the preferred site of PRMT3. The broad localization pattern may implicate the diverse roles of PRMT3 in the cellular setting. The revelation of PRMT3 targets and the transformative character of BPPM for other PRMTs present unprecedented pathways toward elucidating physiological and pathological roles of diverse PRMTs.
journal_name
ACS Chem Bioljournal_title
ACS chemical biologyauthors
Guo H,Wang R,Zheng W,Chen Y,Blum G,Deng H,Luo Mdoi
10.1021/cb4008259subject
Has Abstractpub_date
2014-02-21 00:00:00pages
476-84issue
2eissn
1554-8929issn
1554-8937journal_volume
9pub_type
杂志文章abstract::Complexity generation in naturally occurring peptide scaffolds can occur either by posttranslational modifications of nascent ribosomal proteins or through post assembly line tailoring of nonribosomal peptides. Short enzymatic pathways utilizing bimodular and trimodular nonribosomal peptide synthetase (NRPS) assembly ...
journal_title:ACS chemical biology
pub_type: 杂志文章,评审
doi:10.1021/cb4001684
更新日期:2013-07-19 00:00:00
abstract::Nephronectin is an extracellular matrix protein that interacts with the α8β1 integrin receptor and plays a role in tissue and organ development, though the motifs that mediate adhesion to the receptor remain unclear. This paper describes the use of self-assembled monolayers to study the adhesion of α8β1-presenting cel...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb200186j
更新日期:2011-10-21 00:00:00
abstract::Cell-permeable small molecules can be used to modulate protein function selectively, rapidly, reversibly, and conditionally with temporal and quantitative control in biological systems. The identification of these chemical probes can require the screening of large numbers of small molecules. With the advent of new tec...
journal_title:ACS chemical biology
pub_type: 杂志文章,评审
doi:10.1021/cb600321j
更新日期:2007-01-23 00:00:00
abstract::Siderophores are iron-chelating molecules produced by microorganisms and plants to acquire exogenous iron. Siderophore biosynthetic enzymology often produces elaborate and unique molecules through unusual reactions to enable specific recognition by the producing organisms. Herein, we report the structure of two sidero...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.0c00809
更新日期:2021-01-15 00:00:00
abstract::The goal of incorporating renewable carbon into the fuel and chemical enterprise will most likely be successful when combined systems of biocatalysts and chemical catalysts are exploited. Significant efforts in the biocatalytic release of sugars from biomass are being pursued for subsequent use in fermentation. Two re...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb7001522
更新日期:2007-08-17 00:00:00
abstract::Originally discovered as part of an adaptive bacterial defense system against the invasion of foreign phages, programmable CRISPR-Cas nucleases have emerged as remarkable enzymes with transformative potential for both biological research and clinical application. CRISPR-Cas nucleases likely evolved in their natural co...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.7b00847
更新日期:2018-02-16 00:00:00
abstract::Bromodomains are protein modules that bind to acetylated lysine residues. Their interaction with histone proteins suggests that they function as "readers" of histone lysine acetylation, a component of the proposed "histone code". Bromodomain-containing proteins are often found as components of larger protein complexes...
journal_title:ACS chemical biology
pub_type: 杂志文章,评审
doi:10.1021/cb500996u
更新日期:2015-01-16 00:00:00
abstract::A two-way colorimetric biosensor based on unmodified gold nanoparticles (GNPs) and a switchable double-stranded DNA (dsDNA) concatemer have been demonstrated. Two hairpin probes (H1 and H2) were first designed that provided the fuels to assemble the dsDNA concatemers via hybridization chain reaction (HCR). A functiona...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.7b00060
更新日期:2017-05-19 00:00:00
abstract::Spinal muscular atrophy (SMA) is caused by deletion or mutation of both copies of the SMN1 gene, which produces an essential protein known as SMN. The severity of SMA is modified by variable copy number of a second gene,SMN2, which produces an mRNA that is incorrectly spliced with deletion of the last exon. We describ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb800120t
更新日期:2008-11-21 00:00:00
abstract::Kinases constitute an important class of therapeutic targets being explored both by academia and the pharmaceutical industry. The major focus of this effort was directed toward the identification of ATP competitive inhibitors. Although it has long been recognized that the intracellular concentration of ATP is very dif...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb5002125
更新日期:2014-07-18 00:00:00
abstract::Matrix metalloproteases (MMPs) are a large family of zinc-dependent endopeptidases involved in a diverse set of physiological and pathological processes, most notably in cancer. Current methods for imaging and quantifying MMP activity lack sufficient selectivity and spatiotemporal resolution to allow studies of specif...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.8b00562
更新日期:2018-09-21 00:00:00
abstract::Access to well-defined ubiquitin conjugates has been key to elucidating the biochemical functions of proteins in the ubiquitin signaling network. Yet, we have a poor understanding of how deubiquitinases and ubiquitin-binding proteins respond to ubiquitin modifications when anchored to a protein other than ubiquitin or...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.8b00759
更新日期:2018-09-21 00:00:00
abstract::The canonical NF-κB signaling pathway is a mediator of the cellular inflammatory response and a target for developing therapeutics for multiple human diseases. The furthest downstream proteins in the pathway, the p50/p65 transcription factor heterodimer, have been recalcitrant toward small molecule inhibition despite ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.6b00751
更新日期:2017-01-20 00:00:00
abstract::Dicamba monooxygenase (DMO) catalyzes the O-demethylation of dicamba (3,6-dichloro-2-methoxybenzoate) to produce 3,6-dichlorosalicylate and formaldehyde. Recent crystallographic studies suggest that DMO catalyzes the challenging oxidation of a saturated C-H bond within the methyl group of dicamba to form a hemiacetal ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb400154a
更新日期:2013-08-16 00:00:00
abstract::Benzodiazepines are clinically relevant drugs that bind to GABAA neurotransmitter receptors at the α+/γ2- interfaces and thereby enhance GABA-induced chloride ion flux leading to neuronal hyperpolarization. However, the structural basis of benzodiazepine interactions with their high-affinity site at GABAA receptors is...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.8b00144
更新日期:2018-08-17 00:00:00
abstract::Ubiquitin specific protease 7 (USP7) regulates the protein stability of key cellular regulators in pathways ranging from apoptosis to neuronal development, making it a promising therapeutic target. Here we used an engineered, activated variant of the USP7 catalytic domain to perform structure-activity studies of elect...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.0c00031
更新日期:2020-06-19 00:00:00
abstract::The neurotoxin saxitoxin and related paralytic shellfish toxins are produced by multiple species of cyanobacteria and dinoflagellates. This study investigates the two saxitoxin-producing strains of Scytonema crispum, CAWBG524 and CAWBG72, isolated in New Zealand. Each strain was previously reported to have a distinct ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.8b00608
更新日期:2018-11-16 00:00:00
abstract::Mutations that constitutively activate the phosphatidyl-inositol-3-kinase (PI3K) signaling pathway, including alterations in PI3K, PTEN, and AKT, are found in a variety of human cancers, implicating the PI3K lipid kinase as an attractive target for the development of therapeutic agents to treat cancer and other relate...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb800039y
更新日期:2008-05-16 00:00:00
abstract::Chemical genetics is a powerful approach for identifying therapeutically active small molecules, but identifying the mechanisms of action underlying hit compounds remains challenging. Chemoproteomic platforms have arisen to tackle this challenge and enable rapid mechanistic deconvolution of small-molecule screening hi...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.8b00381
更新日期:2018-08-17 00:00:00
abstract::Prenylated indole alkaloid okaramines selectively target insect glutamate-gated chloride channels (GluCls). Because of their highly complex structures, including azocine and azetidine rings, total synthesis of okaramine A or B has not been achieved, preventing evaluation of the biological activities of okaramines. Bio...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.7b00878
更新日期:2018-03-16 00:00:00
abstract::FAT10 is a ubiquitin-like protein suggested to target proteins for proteasomal degradation. It is highly upregulated upon pro-inflammatory cytokines, namely, TNFα, IFNγ, and IL6, and was found to be highly expressed in various epithelial cancers. Evidence suggests that FAT10 is involved in cancer development and may h...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.9b00667
更新日期:2019-12-20 00:00:00
abstract::Combination therapies that enhance efficacy or permit reduced dosages to be administered have seen great success in a variety of therapeutic applications. More fundamentally, the discovery of epistatic pathway interactions not only informs pharmacologic intervention but can be used to better understand the underlying ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb2003225
更新日期:2011-12-16 00:00:00
abstract::A Natural Compound Library containing myxobacterial secondary metabolites was screened in murine macrophages for novel activators of IL-1β maturation and secretion. The most potent of three hits in total was a so far undescribed metabolite, which was identified from the myxobacterium Hyalangium minutum strain Hym3. Wh...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.8b00659
更新日期:2018-10-19 00:00:00
abstract::Drug optimization is guided by biophysical methods with increasing popularity. In the context of lead structure modifications, the introduction of methyl groups is a simple but potentially powerful approach. Hence, it is crucial to systematically investigate the influence of ligand methylation on biophysical character...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.9b00476
更新日期:2019-12-20 00:00:00
abstract::The publication of the first high-resolution crystal structure of a eukaryotic Cys-loop receptor, GluClα, has provided valuable structural information on this important class of ligand-gated ion channels (LGIC). However, limited functional data exist for the GluCl receptors. Before applying the structural insights fro...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb500323d
更新日期:2014-10-17 00:00:00
abstract::Ascarosides are small-molecule signals that play a central role in C. elegans biology, including dauer formation, aging, and social behaviors, but many aspects of their biosynthesis remain unknown. Using automated 2D NMR-based comparative metabolomics, we identified ascaroside ethanolamides as shunt metabolites in C. ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb3004644
更新日期:2013-02-15 00:00:00
abstract::In urodele amphibians, an early step in limb regeneration is skeletal muscle fiber dedifferentiation into a cellulate that proliferates to contribute new limb tissue. However, mammalian muscle cannot dedifferentiate after injury. We have developed a novel, small-molecule-based method to induce dedifferentiation in mam...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb200532v
更新日期:2012-04-20 00:00:00
abstract::Transcriptomes provide a myriad of potential RNAs that could be the targets of therapeutics or chemical genetic probes of function. Cell-permeable small molecules, however, generally do not exploit these targets, owing to the difficulty in the design of high affinity, specific small molecules targeting RNA. As part of...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb400265y
更新日期:2013-10-18 00:00:00
abstract::Autophagy is a bulk, nonspecific protein degradation pathway that is involved in the pathogenesis of cancer and neurodegenerative disease. Here, we observed that xanthohumol (XN), a prenylated chalcone present in hops (Humulus lupulus L.) and beer, modulates autophagy. By using XN-immobilized beads, valosin-containing...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb200492h
更新日期:2012-05-18 00:00:00
abstract::Fe(III) delivery from blood plasma to cells via the transferrin (Tf) cycle was studied intensively due to its crucial role in Fe homeostasis. Tf-cycle disruptions are linked to anemia, infections, immunodeficiency, and neurodegeneration. Biolayer interferometry (BLI) enabled direct kinetic and thermodynamic measuremen...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.8b01100
更新日期:2019-05-17 00:00:00