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Substrate promiscuity of inositol 1,4,5-trisphosphate kinase driven by structurally-modified ligands and active site plasticity.
D-myo-inositol 1,4,5-trisphosphate (InsP3) is a fundamental second messenger in cellular Ca2+ mobilization. InsP3 3-kinase, a highly specific enzyme binding InsP3 in just one mode, phosphorylates InsP3 specifically at its secondary 3-hydroxyl group to generate a tetrakisphosphate. Using a chemical biology appr…
Diversification in the inositol tris/tetrakisphosphate kinase (ITPK) family: crystal structure and enzymology of the outlier AtITPK4.
Myo-inositol tris/tetrakisphosphate kinases (ITPKs) catalyze diverse phosphotransfer reactions with myo-inositol phosphate and myo-inositol pyrophosphate substrates. However, the lack of structures of nucleotide-coordinated plant ITPKs thwarts a rational understanding of phosphotransfer reactions of the fami…
Modulation of the substrate specificity of the kinase PDK1 by distinct conformations of the full-length protein.
The activation of at least 23 different mammalian kinases requires the phosphorylation of their hydrophobic motifs by the kinase PDK1. A linker connects the phosphoinositide-binding PH domain to the catalytic domain, which contains a docking site for substrates called the PIF pocket. Here, we used a chemical bi…
Quantal Ca2+ release mediated by very few IP3 receptors that rapidly inactivate allows graded responses to IP3.
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels that link extracellular stimuli to Ca2+ signals. Ca2+ release from intracellular stores is "quantal": low IP3 concentrations rapidly release a fraction of the stores. Ca2+ release then slows or terminates without compromising responses t…
Multiple substrate recognition by yeast diadenosine and diphosphoinositol polyphosphate phosphohydrolase through phosphate clamping.
The yeast diadenosine and diphosphoinositol polyphosphate phosphohydrolase DDP1 is a Nudix enzyme with pyrophosphatase activity on diphosphoinositides, dinucleotides, and polyphosphates. These substrates bind to diverse protein targets and participate in signaling and metabolism, being essential for energy…
Covalent penicillin-protein conjugates elicit anti-drug antibodies that are clonally and functionally restricted.
Many archetypal and emerging classes of small-molecule therapeutics form covalent protein adducts. In vivo, both the resulting conjugates and their off-target side-conjugates have the potential to elicit antibodies, with implications for allergy and drug sequestration. Although β-lactam antibiotics are a drug c…
Multi-molecule reaction of serum albumin can occur through thiol-yne coupling.
The free-radical hydrothiolation of alkynes (thiol-yne coupling, TYC) unites two thiol fragments across the carbon-carbon triple bond to give a dithioether derivative with exclusive 1,2-addition; this reaction can be used for modification of peptides and proteins allowing glycoconjugation and fluorescent labeling…
LanCLs add glutathione to dehydroamino acids generated at phosphorylated sites in the proteome.
Enzyme-mediated damage repair or mitigation, while common for nucleic acids, is rare for proteins. Examples of protein damage are elimination of phosphorylated Ser/Thr to dehydroalanine/dehydrobutyrine (Dha/Dhb) in pathogenesis and aging. Bacterial LanC enzymes use Dha/Dhb to form carbon-sulf…
Post-translational insertion of boron in proteins to probe and modulate function.
Boron is absent in proteins, yet is a micronutrient. It possesses unique bonding that could expand biological function including modes of Lewis acidity not available to typical elements of life. Here we show that post-translational Cβ-Bγ bond formation provides mild, direct, site-selective access to the minimally…
Realizing the Promise of Chemical Glycobiology.
Chemical glycobiology is emerging as one of the most uniquely powerful sub-disciplines of chemical biology. The previous scarcity of chemical strategies and the unparalleled structural diversity have created a uniquely fertile ground that is both rich in challenges and potentially very profound in implications. Glyc…
Pathogen-sugar interactions revealed by universal saturation transfer analysis.
Many pathogens exploit host cell-surface glycans. However, precise analyses of glycan ligands binding with heavily modified pathogen proteins can be confounded by overlapping sugar signals and/or compounded with known experimental constraints. Universal saturation transfer analysis (uSTA) builds on e…
Carbon-Centered Radicals in Protein Manipulation.
Methods to directly post-translationally modify proteins are perhaps the most straightforward and operationally simple ways to create and study protein post-translational modifications (PTMs). However, precisely altering or constructing the C-C scaffolds pervasive throughout biology is difficult with common two-e…
Intact nucleosomal context enables chromodomain reader MRG15 to distinguish H3K36me3 from -me2
A wealth of in vivo evidence demonstrates the physiological importance of histone H3 trimethylation at lysine 36 (H3K36me3), to which chromodomain-containing proteins, such as MRG15, bind preferentially compared to their dimethyl (H3K36me2) counterparts. However, in vitro studies using isolated H3 p…
Small molecule modulation of a redox-sensitive stress granule protein dissolves stress granules with beneficial outcomes for familial amyotrophic lateral sclerosis models
Neurodegeneràve diseases such as amyotrophic lateral sclerosis (ALS) are oten associated with mutàons in proteins that are associated with stress granules. Stress granules are condensates formed by liquid-liquid phase separàon which, when aberrant, can lead to altered condensàon behaviours and disease phe…
Direct radical functionalization of native sugars.
Naturally occurring (native) sugars and carbohydrates contain numerous hydroxyl groups of similar reactivity1,2. Chemists, therefore, rely typically on laborious, multi-step protecting-group strategies3 to convert these renewable feedstocks into reagents (glycosyl donors) to make glycans. The direct transf…
The least common multiple of consecutive arithmetic progression terms
AbstractLet k ≥ 0, a ≥ 1 and b ≥ 0 be integers. We define the arithmetic function gk,a,b for any positive integer n byIf we let a = 1 and b = 0, then gk,a,b becomes the arithmetic function that was previously introduced by Farhi. Farhi proved that gk,1,0 is periodic and that k! is a period. Hong and Yang improve…