Significance Biological roles of inorganic phosphate require careful regulation its transport across cell membranes, but mechanisms are poorly understood. We demonstrate that a major cellular export protein, XPR1, is regulated by the most “energetic” signaling molecules—1,5-bisdiphosphoinositol 1,2,3,4-tetrakisphosphate (InsP 8 ). derive this conclusion showing reduced XPR1-mediated efflux when InsP synthesis was attenuated genetic or pharmacological techniques; rescued using liposomes to...

Many proteins involved in eukaryotic phosphate homeostasis are regulated by SPX domains. In yeast, the vacuolar transporter chaperone (VTC) complex contains two such domains, but mechanistic details of its regulation not well understood. Here, we show at atomic level how inositol pyrophosphates interact with domains subunits Vtc2 and Vtc3 to control activity VTC complex. inhibits catalytically active subunit Vtc4 homotypic SPX-SPX interactions via conserved helix α1 previously undescribed...

Here we report on the use of a silanol-decorated polyoxotungstate, [SbW9O33(tBuSiOH)3]3– (1), as molecular support to describe coordination vanadium atom at single-site silica surfaces. By reacting [V(Mes)3·thf] (Mes = 2,4,6-trimethylphenyl) with 1 in tetrahydrofuran, vanadium(III) derivative [SbW9O33(tBuSiO)3V(thf)]3– (2) was obtained. Compound 2 displays paramagnetic behavior expected for d2-VIII high spin complex (SQUID measurements) triplet electronic ground state (ca. 30 kcal·mol–1 more...

Significance Improved understanding of the epitranscriptomic control process will help decipher regulation global gene expression. Here, we demonstrate that cell-signaling inositol pyrophosphate 5-InsP 7 stabilizes mRNAs are normally committed to decay pathways by NUDT3-mediated removal protective 5′ cap. We demonstrated this effect in vitro using recombinant NUDT3. Then, applied pharmacological, genetic, and chemical tools manipulate cellular levels , thereby showing it enhance mRNA...

Nudix hydrolases attract considerable attention for their wide range of specialized activities in all domains life. One particular group phosphohydrolases (DIPPs), through metabolism diphosphoinositol polyphosphates (PP-InsPs), regulates the actions these upon bioenergetic homeostasis. In current study, we describe, at an atomic level, hitherto unknown properties human DIPP1.We provide X-ray analysis catalytic core DIPP1 crystals complexed with either natural PP-InsPs, alternative PP-InsP...

Intracellular biochemical reactions are often localized in space and time, inducing gradients of enzymatic activity that may play decisive roles determining cell's fate functions. However, the techniques available to examine such remain limited. Here, we propose a new method engineer spatial gradient signaling protein concentration within Xenopus egg extracts using superparamagnetic nanoparticles. We show that, upon application magnetic field, nanoparticles with tunable length extension is...

We present here the most active synthetic Ni superoxide dismutase (NiSOD) mimic reported to date. Reactive oxygen species are aggressive compounds, which concentrations tightly regulated in vivo. Among them, anion, O

The cellular level of reactive oxygen species (ROS) has to be controlled avoid some pathologies, especially those linked oxidative stress. One strategy for designing antioxidants consists modeling natural enzymes involved in ROS degradation. Among them, nickel superoxide dismutase (NiSOD) catalyzes the dismutation radical anion, O2•-, into O2 and H2O2. We report here Ni complexes with tripeptides derived from amino-terminal CuII- NiII-binding (ATCUN) motif that mimics structural features...

Inositol poly- and pyrophosphates (InsPs PP-InsPs) are densely phosphorylated eukaryotic messengers, which involved in numerous cellular processes. To elucidate their signaling functions at the molecular level, non-hydrolyzable bisphosphonate analogs of inositol pyrophosphates, PCP-InsPs, have been instrumental. Here, an efficient synthetic strategy to obtain these unprecedented quantities is described - relying on use combined phosphate ester-phosphoramidite reagents. The PCP-analogs,...

Abstract Determining the affinity of proteins for uranyl is key to understand toxicity this cation and further develop decorporation strategies. However, usual techniques achieve that goal often require specific equipment expertise. Here, we propose a simple, efficient, fluorescence‐based method assess peptides uranyl, at equilibrium in buffered solution. We first designed characterized an original uranyl‐binding fluorescent probe. then built reference scale solution, relying on signal...

Living systems offer attractive strategies to generate nanoscale structures because of their innate functional properties such as the dynamic assembly ordered nanometer fibers, generation mechanical forces, or directional transport mediated by molecular motors. The design hybrid systems, capable interfacing artificial building blocks with biomolecules, may be a key step toward rational devices and materials. Here, we have designed bottom-up approach organize cytoskeletal elements in space...

A joint experimental and molecular simulation study was performed to investigate the adsorption of tetrachloroethene on two MFI zeolites, ZSM-5 with a Si/Al ratio 26.5, silicalite-1, which is pure silica form ZSM-5. Adsorption isotherms isosteric heats were measured compared results. Experimental curves for both zeolites show step at loading 4 molecules·uc−1 that interpreted in terms structural change host framework. thermodynamic analysis based osmotic ensemble scheme allowed attributing...

A heteroditopic ligand H(2)-L consisting of a dihydroxybenzene (catechol)-unit linked via an amide bond to pyridyl-unit and its methyl-protected precursor Me(2)-L were synthesized, characterized, their photophysical properties investigated. The three accessible protonation states the ligand, H(3)-L(+), H(2)-L, H-L(-), showed distinct (1)H NMR, absorption emission spectroscopic characteristics that allow pH-sensing. signatures obtained act as guide understand signaling mechanism luminescent...

Abstract Inositol hexakisphosphate kinases (IP6Ks) are emerging as relevant pharmacological targets because a multitude of disease-related phenotypes has been associated with their function. While the development potent IP6K inhibitors is gaining momentum, tool to distinguish mammalian isozymes still lacking. Here, we implemented an analog-sensitive approach for IP6Ks and performed high-throughput screen identify suitable lead compounds. The most promising hit, FMP-201300, exhibited high...

Inositol pyrophosphates (PP-IPs) are densely phosphorylated messenger molecules involved in numerous biological processes. PP-IPs contain one or two pyrophosphate group(s) attached to a myo-inositol ring. 5PP-IP

Nudix hydrolases, an enzyme superfamily with representatives in all classes of organisms, possess a conserved catalytic sequence (Nudix motif), GX5EX7REUXEEXGU, where ‘U’ designates hydrophobic residue. The Diphosphoinositol Polyphosphate Phosphohydrolases (DIPPs) represent one subgroup the family. By metabolizing diphosphoinositol polyphosphates (PP-InsPs), DIPPs switch-off their signaling activities that regulate metabolic homeostasis. However, there has not been molecular rationalization...

Abstract We present here the most active synthetic Ni superoxide dismutase (NiSOD) mimic reported to date. Reactive oxygen species are aggressive compounds, which concentrations tightly regulated in vivo. Among them, anion, O 2 ⋅ − , is controlled by dismutases. Capitalizing on versatility of Amino‐Terminal Cu II ‐ and ‐binding (ATCUN) peptide motif, we introduced positive charges around center favor interaction with radical anion. At physiological pH, pentapeptide H−Cys−His−Cys−Arg−Arg−NH...

Abstract Maintaining tightly copper homeostasis is crucial for the survival of all living organisms, in particular microorganisms like bacteria. They have evolved a number proteins to capture, transport and deliver Cu(I), while avoiding Fenton‐like reactions. Some Cu exhibit methionine‐rich (Met‐rich) domains, whose role remains elusive. In this work, we designed biomimetic compounds recapitulating possible Cu(I) binding sites these order examine parameters important binding. Five different...

Inositol hexakisphosphate kinases (IP6Ks) are emerging as relevant pharmacological targets because a multitude of disease-related phenotypes has been associated with their function. While the development potent IP6K inhibitors is gaining momentum, tool to distinguish mammalian isozymes still lacking. Here, we implemented an analog-sensitive approach for IP6Ks and performed high-throughput screen identify suitable lead compounds. The most promising hit, FMP-201300, exhibited high potency...

Inositol hexakisphosphate kinases (IP6Ks) are emerging as relevant pharmacological targets because a multitude of disease-related phenotypes has been associated with their function. While the development potent IP6K inhibitors is gaining momentum, tool to distinguish mammalian isozymes still lacking. Here, we implemented an analog-sensitive approach for IP6Ks and performed high-throughput screen identify suitable lead compounds. The most promising hit, FMP-201300, exhibited high potency...