Abstract:
:The JmjC histone demethylases (KDMs) are linked to tumour cell proliferation and are current cancer targets; however, very few highly selective inhibitors for these are available. Here we report cyclic peptide inhibitors of the KDM4A-C with selectivity over other KDMs/2OG oxygenases, including closely related KDM4D/E isoforms. Crystal structures and biochemical analyses of one of the inhibitors (CP2) with KDM4A reveals that CP2 binds differently to, but competes with, histone substrates in the active site. Substitution of the active site binding arginine of CP2 to N-ɛ-trimethyl-lysine or methylated arginine results in cyclic peptide substrates, indicating that KDM4s may act on non-histone substrates. Targeted modifications to CP2 based on crystallographic and mass spectrometry analyses results in variants with greater proteolytic robustness. Peptide dosing in cells manifests KDM4A target stabilization. Although further development is required to optimize cellular activity, the results reveal the feasibility of highly selective non-metal chelating, substrate-competitive inhibitors of the JmjC KDMs.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Kawamura A,Münzel M,Kojima T,Yapp C,Bhushan B,Goto Y,Tumber A,Katoh T,King ON,Passioura T,Walport LJ,Hatch SB,Madden S,Müller S,Brennan PE,Chowdhury R,Hopkinson RJ,Suga H,Schofield CJdoi
10.1038/ncomms14773subject
Has Abstractpub_date
2017-04-06 00:00:00pages
14773issn
2041-1723pii
ncomms14773journal_volume
8pub_type
杂志文章abstract::Modular and orthogonal genetic logic gates are essential for building robust biologically based digital devices to customize cell signalling in synthetic biology. Here we constructed an orthogonal AND gate in Escherichia coli using a novel hetero-regulation module from Pseudomonas syringae. The device comprises two co...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/ncomms1516
更新日期:2011-10-18 00:00:00
abstract::The evolutionary progression from primary to metastatic prostate cancer is largely uncharted, and the implications for liquid biopsy are unexplored. We infer detailed reconstructions of tumor phylogenies in ten prostate cancer patients with fatal disease, and investigate them in conjunction with histopathology and tum...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/s41467-020-18843-5
更新日期:2020-10-08 00:00:00
abstract::The sensitivity of quantum magnetometer is challenged by control errors and, especially in the solid state, by their short coherence times. Refocusing techniques can overcome these limitations and improve the sensitivity to periodic fields, but they come at the cost of reduced bandwidth and cannot be applied to sense ...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/ncomms2375
更新日期:2013-01-01 00:00:00
abstract::The possibility of measuring binding of small-molecule drugs to desired targets in live cells could provide a better understanding of drug action. However, current approaches mostly yield static data, require lysis or rely on indirect assays and thus often provide an incomplete understanding of drug action. Here, we p...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/ncomms4946
更新日期:2014-05-28 00:00:00
abstract::Protein-protein interactions featuring intricate binding epitopes remain challenging targets for synthetic inhibitors. Interactions of NEMO, a scaffolding protein central to NF-κB signaling, exemplify this challenge. Various regulators are known to interact with different coiled coil regions of NEMO, but the topologic...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/s41467-020-15576-3
更新日期:2020-04-14 00:00:00
abstract::Advances in chemistry and massively parallel detection underlie DNA-sequencing platforms that are poised for application in personalized medicine. In stark contrast, systematic generation of protein-level data lags well behind genomics in virtually every aspect: depth of coverage, throughput, ease of sample preparatio...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/ncomms3171
更新日期:2013-01-01 00:00:00
abstract::Most estimates of the burden of malaria are based on its direct impacts; however, its true burden is likely to be greater because of its wider effects on overall health. Here we estimate the indirect impact of malaria on children's health in a case-control study, using the sickle cell trait (HbAS), a condition associa...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/s41467-019-08775-0
更新日期:2019-02-20 00:00:00
abstract::Bacterial contamination of biological channels, catheters or water resources is a major threat to public health, which can be amplified by the ability of bacteria to swim upstream. The mechanisms of this 'rheotaxis', the reorientation with respect to flow gradients, are still poorly understood. Here, we follow individ...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/s41467-019-11360-0
更新日期:2019-07-31 00:00:00
abstract::Methanol is a biotechnologically promising substitute for food and feed substrates since it can be produced renewably from electricity, water and CO2. Although progress has been made towards establishing Escherichia coli as a platform organism for methanol conversion via the energy efficient ribulose monophosphate (Ru...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/s41467-020-19235-5
更新日期:2020-10-26 00:00:00
abstract::The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discoverin...
journal_title:Nature communications
pub_type: 杂志文章,meta分析
doi:10.1038/s41467-020-15706-x
更新日期:2020-05-21 00:00:00
abstract::The competition between bimolecular nucleophilic substitution and base-induced elimination is of fundamental importance for the synthesis of pure samples in organic chemistry. Many factors that influence this competition have been identified over the years, but the underlying atomistic dynamics have remained difficult...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/s41467-017-00065-x
更新日期:2017-06-21 00:00:00
abstract::The basal ganglia, and the striatum in particular, have been implicated in the generation of contraversive movements. The striatum projects to downstream basal ganglia nuclei through two main circuits, originating in striatonigral and striatopallidal neurons, and different models postulate that the two pathways can wo...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/ncomms5315
更新日期:2014-07-08 00:00:00
abstract::Inferring neural mechanisms from functional magnetic resonance imaging (fMRI) is challenging because the fMRI signal integrates over millions of neurons. One approach is to compare computational models that map neural activity to fMRI responses, to see which best predicts fMRI data. We use this approach to compare fou...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/s41467-018-05957-0
更新日期:2018-09-21 00:00:00
abstract::Previous research has focused on feeding circuits residing in the hindbrain and midbrain that govern homeostatic or hedonic control of food intake. However, the feeding circuits controlling emotional or cognitive aspects of food intake are largely unknown. Here we use chemical genetics and optogenetic techniques to di...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/ncomms10188
更新日期:2015-12-15 00:00:00
abstract::Human gut microbiome is a promising target for managing type 2 diabetes (T2D). Measures altering gut microbiota like oral intake of probiotics or berberine (BBR), a bacteriostatic agent, merit metabolic homoeostasis. We hence conducted a randomized, double-blind, placebo-controlled trial with newly diagnosed T2D patie...
journal_title:Nature communications
pub_type: 杂志文章,随机对照试验
doi:10.1038/s41467-020-18414-8
更新日期:2020-10-06 00:00:00
abstract::Shaping ceramics into complex and intricate geometries using cost-effective processes is desirable in many applications but still remains an open challenge. Inspired by plant seed dispersal units that self-fold on differential swelling, we demonstrate that self-shaping can be implemented in ceramics by programming the...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/ncomms13912
更新日期:2016-12-23 00:00:00
abstract::Macrophages play a pivotal role in tissue fibrogenesis, which underlies the pathogenesis of many end-stage chronic inflammatory diseases. MicroRNAs are key regulators of immune cell functions, but their roles in macrophage's fibrogenesis have not been characterized. Here we show that IL-4 and IL-13 induce miR-142-5p a...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/ncomms9523
更新日期:2015-10-05 00:00:00
abstract::Membrane-bound pyrophosphatases (M-PPases), which couple proton/sodium ion transport to pyrophosphate synthesis/hydrolysis, are important in abiotic stress resistance and in the infectivity of protozoan parasites. Here, three M-PPase structures in different catalytic states show that closure of the substrate-binding p...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/ncomms13596
更新日期:2016-12-06 00:00:00
abstract::Although the amyloid β-protein (Aβ) is believed to play an initiating role in Alzheimer's disease (AD), the molecular characteristics of the key pathogenic Aβ forms are not well understood. As a result, it has proved difficult to identify optimal agents that target disease-relevant forms of Aβ. Here, we combined the u...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/s41467-018-05068-w
更新日期:2018-07-11 00:00:00
abstract::In Arabidopsis thaliana, CONSTANS (CO) plays an essential role in the regulation of photoperiodic flowering under long-day conditions. CO protein is stable only in the afternoon of long days, when it induces the expression of FLOWERING LOCUS T (FT), which promotes flowering. The blue-light photoreceptor FLAVIN-BINDING...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/s41467-017-02476-2
更新日期:2017-12-22 00:00:00
abstract::Carbon forms one of nature's strongest chemical bonds; its allotropes having provided some of the most exciting scientific discoveries in recent times. The possibility of inter-allotropic transformations/hybridization of carbon is hence a topic of immense fundamental and technological interest. Such modifications usua...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/ncomms5941
更新日期:2014-09-15 00:00:00
abstract::Myoblast fusion (MF) is required for muscle growth and repair, and its alteration contributes to muscle diseases. The mechanisms governing this process are incompletely understood, and no epigenetic regulator has been previously described. Ash1L is an epigenetic activator belonging to the Trithorax group of proteins a...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/s41467-018-07313-8
更新日期:2018-11-28 00:00:00
abstract:: ...
journal_title:Nature communications
pub_type: 社论
doi:10.1038/s41467-018-07733-6
更新日期:2018-12-10 00:00:00
abstract::Following microbial pathogen invasion, one of the main challenges for the host is to rapidly control pathogen spreading to avoid vital tissue damage. Here we report that an effector CD8(+) T-cell population that expresses the marker NK1.1 undergoes delayed contraction and sustains early anti-microbial protection. NK1....
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/ncomms6150
更新日期:2014-10-06 00:00:00
abstract::Palaeo data suggest that Greenland must have been largely ice free during Marine Isotope Stage 11 (MIS-11). However, regional summer insolation anomalies were modest during this time compared to MIS-5e, when the Greenland ice sheet likely lost less volume. Thus it remains unclear how such conditions led to an almost c...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/ncomms16008
更新日期:2017-07-06 00:00:00
abstract::A phase transition is often accompanied by the appearance of an order parameter and symmetry breaking. Certain magnetic materials exhibit exotic hidden-order phases, in which the order parameters are not directly accessible to conventional magnetic measurements. Thus, experimental identification and theoretical unders...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/s41467-019-12410-3
更新日期:2019-10-08 00:00:00
abstract::Carminic acid, a glucosylated anthraquinone found in scale insects like Dactylopius coccus, has since ancient times been used as a red colorant in various applications. Here we show that a membrane-bound C-glucosyltransferase, isolated from D. coccus and designated DcUGT2, catalyzes the glucosylation of flavokermesic ...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/s41467-017-02031-z
更新日期:2017-12-07 00:00:00
abstract::Biological cellular structures have inspired many scientific disciplines to design synthetic structures that can mimic their functions. Here, we closely emulate biological cellular structures in a rationally designed synthetic multicellular hybrid ion pump, composed of hydrogen-bonded [EMIM+][TFSI-] ion pairs on the s...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/s41467-019-11973-5
更新日期:2019-09-05 00:00:00
abstract::Ti-alloys represent the principal structural materials in both aerospace development and metallic biomaterials. Key to optimizing their mechanical and functional behaviour is in-depth know-how of their phases and the complex interplay of diffusive vs. displacive phase transformations to permit the tailoring of intrica...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/s41467-017-01578-1
更新日期:2017-11-10 00:00:00
abstract::Human pressures on the ocean are thought to be increasing globally, yet we know little about their patterns of cumulative change, which pressures are most responsible for change, and which places are experiencing the greatest increases. Managers and policymakers require such information to make strategic decisions and...
journal_title:Nature communications
pub_type: 杂志文章
doi:10.1038/ncomms8615
更新日期:2015-07-14 00:00:00