Browse
Submit Data
Databases
API
Help

Dataset Information

7 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Activation by substoichiometric inhibition.

ABSTRACT: Startling reports described the paradoxical triggering of the human mitogen-activated protein kinase pathway when a small-molecule inhibitor specifically inactivates the BRAF V600E protein kinase but not wt-BRAF. We performed a conceptual analysis of the general phenomenon "activation by inhibition" using bacterial and human HtrA proteases as models. Our data suggest a clear explanation that is based on the classic biochemical principles of allostery and cooperativity. Although substoichiometric occupancy of inhibitor binding sites results in partial inhibition, this effect is overrun by a concomitant activation of unliganded binding sites. Therefore, when an inhibitor of a cooperative enzyme does not reach saturating levels, a common scenario during drug administration, it may cause the contrary of the desired effect. The implications for drug development are discussed.

SUBMITTER: Merdanovic M

PROVIDER: S-EPMC6983408 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Activation by substoichiometric inhibition.

Merdanovic Melisa M Burston Steven G SG Schmitz Anna Laura AL Köcher Steffen S Knapp Stefan S Clausen Tim T Kaiser Markus M Huber Robert R Ehrmann Michael M

Proceedings of the National Academy of Sciences of the United States of America 20200106 3

Startling reports described the paradoxical triggering of the human mitogen-activated protein kinase pathway when a small-molecule inhibitor specifically inactivates the BRAF V600E protein kinase but not wt-BRAF. We performed a conceptual analysis of the general phenomenon "activation by inhibition" using bacterial and human HtrA proteases as models. Our data suggest a clear explanation that is based on the classic biochemical principles of allostery and cooperativity. Although substoichiometric ...[more]

PMID: 31907318

Similar Datasets

Substoichiometric inhibition of Abeta(1-40) aggregation by a tandem Abeta(40-1-Gly8-1-40) peptide.

Project description:Abeta peptides aggregate to form insoluble and neurotoxic fibrils associated with Alzheimer's disease. Inhibition of the aggregation has been the subject of numerous studies. Here we describe a novel, substoichiometric inhibitor of Abeta(1-40) fibrillization as a tandem dimeric construct consisting of Abeta(40-1) (reverse sequence) linked to Abeta(1-40) via an eight residue glycine linker. At molar ratios of the tandem peptide to Abeta(1-40) of 1:10 to 1:25 inhibition of fibrillization, as measured by ThioflavinT, was observed. We postulate that the tandem construct binds to a fibrillar intermediate but the reverse sequence delays or prevents further monomer association.

| S-EPMC2897963 | biostudies-literature

Substoichiometric ribose methylations in spliceosomal snRNAs

Project description:Sequencing-based profiling of ribose methylations is a new approach that allows for experiments adrressing dynamic changes on a large scale. Here, we apply such a method to spliceosomal snRNAs present in human whole cell RNA. Analysis of solid tissue samples confirmed all previously known sites and demonstrated close to full methylation at almost all sites. Methylation changes were revealed in biological experimental settings, using T cell activation as an example, and in the T cell leukemia model, Jurkat cells. Such changes could impact the dynamics of snRNA interactions during the spliceosome cycle and affect mRNA splicing efficiency and splicing patterns.

2017-10-20 | GSE104947 | GEO

Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses.

Project description:Wild-type and mutant transthyretin (TTR) can misfold and deposit in the heart, peripheral nerves, and other sites causing amyloid disease. Pharmacological chaperones, Tafamidis(®) and diflunisal, inhibit TTR misfolding by stabilizing native tetrameric TTR; however, their minimal effective concentration is in the micromolar range. By immune-targeting sparsely populated TTR misfolding intermediates (i.e. monomers), we achieved fibril inhibition at substoichiometric concentrations. We developed an antibody (misTTR) that targets TTR residues 89-97, an epitope buried in the tetramer but exposed in the monomer. Nanomolar misTTR inhibits fibrillogenesis of misfolded TTR under micromolar concentrations. Pan-specific TTR antibodies do not possess such fibril inhibiting properties. We show that selective targeting of misfolding intermediates is an alternative to native state stabilization and requires substoichiometric concentrations. MisTTR or its derivative may have both diagnostic and therapeutic potential.

| S-EPMC4848561 | biostudies-literature

Substoichiometric hydroxynonenylation of a single protein recapitulates whole-cell-stimulated antioxidant response.

Project description:Lipid-derived electrophiles (LDEs) that can directly modify proteins have emerged as important small-molecule cues in cellular decision-making. However, because these diffusible LDEs can modify many targets [e.g., >700 cysteines are modified by the well-known LDE 4-hydroxynonenal (HNE)], establishing the functional consequences of LDE modification on individual targets remains devilishly difficult. Whether LDE modifications on a single protein are biologically sufficient to activate discrete redox signaling response downstream also remains untested. Herein, using T-REX (targetable reactive electrophiles and oxidants), an approach aimed at selectively flipping a single redox switch in cells at a precise time, we show that a modest level (?34%) of HNEylation on a single target is sufficient to elicit the pharmaceutically important antioxidant response element (ARE) activation, and the resultant strength of ARE induction recapitulates that observed from whole-cell electrophilic perturbation. These data provide the first evidence that single-target LDE modifications are important individual events in mammalian physiology.

| S-EPMC4304447 | biostudies-literature

Substoichiometric ribose methylations in spliceosomal snRNAs

Project description:Substoichiometric ribose methylations in spliceosomal snRNAs

| PRJNA414213 | ENA

Gene regulation by substoichiometric heterocomplex formation of undecameric TRAP and trimeric anti-TRAP.

Project description:The control of tryptophan production in Bacillus is a paradigmatic example of gene regulation involving the interplay of multiple protein and nucleic acid components. Central to this combinatorial mechanism are the homo-oligomeric proteins TRAP (trp RNA-binding attenuation protein) and anti-TRAP (AT). TRAP forms undecameric rings, and AT assembles into triskelion-shaped trimers. Upon activation by tryptophan, the outer circumference of the TRAP ring binds specifically to a series of tandem sequences present in the 5' UTR of RNA transcripts encoding several tryptophan metabolism genes, leading to their silencing. AT, whose expression is up-regulated upon tryptophan depletion to concentrations not exceeding a ratio of one AT trimer per TRAP 11-mer, restores tryptophan production by binding activated TRAP and preventing RNA binding. How the smaller AT inhibitor prevents RNA binding at such low stoichiometries has remained a puzzle, in part because of the large RNA-binding surface on the tryptophan-activated TRAP ring and its high affinity for RNA. Using X-ray scattering, hydrodynamic, and mass spectrometric data, we show that the polydentate action of AT trimers can condense multiple intact TRAP rings into large heterocomplexes, effectively reducing the available contiguous RNA-binding surfaces. This finding reveals an unprecedented mechanism for substoichiometric inhibition of a gene-regulatory protein, which may be a widespread but underappreciated regulatory mechanism in pathways that involve homo-oligomeric or polyvalent components.

| S-EPMC3948263 | biostudies-literature

Long-term Cyclability of Substoichiometric Silicon Nitride Thin Film Anodes for Li-ion Batteries.

Project description:Silicon has been the subject of an extensive research effort aimed at developing new anode materials for lithium ion batteries due to its large specific and volumetric capacity. However, commercial use is limited by a number of degradation problems, many of which are related to the large volume change the material undergoes during cycling in combination with limited lithium-diffusivity. Silicon rich silicon oxides (SiOx), which converts into active silicon and inactive lithium oxide during the initial lithiation, have attracted some attention as a possible solution to these issues. In this work we present an investigation of silicon rich amorphous silicon nitride (a-SiNx) as an alternative convertible anode material. Amorphous SiN0.89 thin films deposited by plasma enhanced chemical vapour deposition show reversible reactions with lithium when cycled between 0.05 and 1.0?V vs. Li+/Li. This material delivers a reversible capacity of approximately 1,200 mAh/g and exhibits excellent cycling stability, with 41?nm a-SiN0.89 thin film electrodes showing negligible capacity degradation over more than 2,400 cycles.

| S-EPMC5645470 | biostudies-literature

Umpolung amide synthesis using substoichiometric N-iodosuccinimide (NIS) and oxygen as a terminal oxidant.

Project description:Umpolung Amide Synthesis (UmAS) provides direct access to amides from an ?-bromo nitroalkane and an amine. Based on its mechanistic bifurcation after convergent C-N bond formation, depending on the absence or presence of oxygen, UmAS using substoichiometric N-iodosuccinimide (NIS) under aerobic conditions has been developed. In combination with the enantioselective preparation of ?-bromo nitroalkane donors, this protocol realizes the goal of enantioselective ?-amino amide and peptide synthesis based solely on catalytic methods.

| S-EPMC4168777 | biostudies-literature

MutS HOMOLOG1 silencing mediates ORF220 substoichiometric shifting and causes male sterility in Brassica juncea.

Project description:Cytoplasmic male sterility (CMS) has consistently been associated with the expression of mitochondrial open reading frames (ORFs) that arise from genomic rearrangements. Spontaneous fertility reversion in CMS has been observed in several cases, but a clear understanding of fertility reversion controlled by nuclear genetic influences has been lacking. Here, we identified spontaneous fertile revertant lines for Brassica juncea CMS cytoplasm in which the mitochondrial genome has undergone substoichiometric shifting (SSS) to suppress ORF220 copy number. We placed ORF220, with or without a mitochondrial targeting presequence, under the control of the CaMV35S and AP3 promoters in Arabidopsis to confirm that ORF220 causes male sterility when mitochondrially localized. We found that copy number of the ORF220 gene was altered under conditions that suppress MSH1, a nuclear gene that controls illegitimate recombination in plant mitochondria. MSH1-RNAi lines with increased ORF220 copy number were male sterile compared with wild type. We found that a wide range of genes involved in anther development were up- and down-regulated in revertant and MSH1-RNAi lines, respectively. The system that we have developed offers valuable future insight into the interplay of MSH1 and SSS in CMS induction and fertility reversion as a mediator of nuclear-mitochondrial crosstalk.

| S-EPMC4682445 | biostudies-literature

Substoichiometric shifting in the plant mitochondrial genome is influenced by a gene homologous to MutS.

Project description:The plant mitochondrial genome is retained in a multipartite structure that arises by a process of repeat-mediated homologous recombination. Low-frequency ectopic recombination also occurs, often producing sequence chimeras, aberrant ORFs, and novel subgenomic DNA molecules. This genomic plasticity may distinguish the plant mitochondrion from mammalian and fungal types. In plants, relative copy number of recombination-derived subgenomic DNA molecules within mitochondria is controlled by nuclear genes, and a genomic shifting process can result in their differential copy number suppression to nearly undetectable levels. We have cloned a nuclear gene that regulates mitochondrial substoichiometric shifting in Arabidopsis. The CHM gene was shown to encode a protein related to the MutS protein of Escherichia coli that is involved in mismatch repair and DNA recombination. We postulate that the process of substoichiometric shifting in plants may be a consequence of ectopic recombination suppression or replication stalling at ectopic recombination sites to effect molecule-specific copy number modulation.

| S-EPMC156310 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data