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Gustav Sundell, Beat Vögeli, Ylva Ivarsson, Celestine Chi
The use of NMR chemical shift perturbation to monitor changes taking place around the binding site of a ligand-protein interaction is a routine and widely applied methodology in the field of protein biochemistry. Shifts are often acquired by titrating various concentrations of ligand to a fixed concentration of the receptor and may serve the purposes, amongst others, to determine affinity constants, locate binding surfaces, or differentiate between binding mechanisms. Shifts are quantified by the so-called combined chemical shift difference...
November 16, 2017: Biochemistry
Victoria A Roberts, Michael E Pique, Simon Hsu, Sheng Li
Protein-protein interactions are essential for biological function, but structures of protein-protein complexes are difficult to obtain experimentally. To derive the protein complex of the DNA-repair enzyme human uracil-DNA-glycosylase (hUNG) with its protein inhibitor (UGI), we combined rigid-body computational docking with hydrogen/deuterium exchange mass spectrometry (DXMS). Computational docking of the unbound protein structures provides a list of possible three-dimensional models of the complex; DXMS identifies solvent-protected protein residues...
November 16, 2017: Biochemistry
Thao Tran, Brian Cannon
Internal loops within structured nucleic acids disrupt local base-stacking and destabilize neighboring helical domains; however, these structural motifs also expand the conformational and functional capabilities for structured nucleic acids. Variations in size, distribution of loop nucleotides on opposing strands (strand asymmetry), and sequence alter their biophysical properties. Here, the thermodynamics and structural flexibility of poly(T)-rich DNA internal loops were systematically investigated in terms of loop size and strand asymmetry...
November 15, 2017: Biochemistry
Nadia Sukusu Nielsen, Dennis Wilkens Juhl, Ebbe Toftgaard Poulsen, Marie V Lukassen, Emil Christian Poulsen, Michael W Risør, Carsten Scavenius, Jan Johannes Enghild
Mutations in the transforming growth factor β-induced protein (TGFBIp) cause phenotypically diverse corneal dystrophies, where protein aggregation in the cornea leads to severe visual impairment. Previous studies have shown a relationship between mutant-specific corneal dystrophy phenotypes and the thermodynamic stability of TGFBIp. Using LC-MS/MS and NMR, we investigated correlations between the structural integrity of disease-related mutants of the fourth FAS1 domain (FAS1-4) and deamidation of TGFBIp residue Asn622...
November 15, 2017: Biochemistry
Ananda Chowdhury, Robert G Brinson, Beiyang Wei, William G Stetler-Stevenson
Tissue Inhibitor of Metalloprotease -2 (TIMP-2) is a secreted 21 kDa multifunctional protein first described as an endogenous inhibitor of matrix metalloproteinases (MMPs) that prevents breakdown of the extracellular matrix often observed in chronic diseases. TIMP-2 diminishes growth factor-mediated cell proliferation in vitro, as well as neoangiogenesis and tumor growth in vivo independent of its MMP-inhibitory activity, . These physiological properties make TIMP-2 an excellent candidate for further pre-clinical development as a biologic therapy of cancer...
November 15, 2017: Biochemistry
Gregory A Grant
Almost all organisms contain the same biosynthetic pathway for the synthesis of l-serine from the glycolytic intermediate, D-3-phosphoglycerate. However, regulation of this pathway varies from organism to organism. Many organisms control the activity of the first enzyme in the pathway, D-3-phosphoglyerate dehydrogenase (PGDH), by feedback inhibition through the interaction of l-serine with the ACT domains within the enzyme. The last enzyme in the pathway, phosphoserine phosphatase (PSP) has also been reported to be inhibited by l-serine...
November 15, 2017: Biochemistry
Karl M Wetterhorn, Kaitlyn Gabardi, Herbert Michlmayr, Alexandra Malachova, Mark Busman, Susan Patricia McCormick, Franz Berthiller, Gerhard Adam, Ivan Rayment
Family 1 UDP-glycosyltransferases in plants (UGTs) primarily form glucose conjugates of small molecules and, besides other functions, play a role in detoxification of xenobiotics. Indeed, overexpression of a barley UGT in wheat has been shown to control Fusarium head blight, where this is a plant disease of global significance that leads to reduced crop yields and contamination with trichothecene mycotoxins such as deoxynivalenol (DON), T-2 toxin and many other structural variants. The UGT Os79 from rice has emerged as a promising candidate for inactivation of mycotoxins on account of its ability to glycosylate DON, nivalenol and hydrolyzed T-2 toxin (HT-2)...
November 15, 2017: Biochemistry
Jitrayut Jitonnom, Joni Mujika, Marc W van der Kamp, Adrian J Mulholland
Creatininase catalyzes the conversion of creatinine (a biosensor for kidney function) to creatine via a two-step mechanism: water-addition followed by ring-opening. Water-addition is common to other known cyclic amidohydrolases, but the precise mechanism for ring-opening is still under debate. The proton donor in this step is either His178, or a water molecule bound to one of metal ions, and the roles of His178 and Glu122 are unclear. Here, the two possible reaction pathways have been fully examined by means of combined quantum mechanics/molecular mechanics simulations at the SCC-DFTB/CHARMM22 level of theory...
November 15, 2017: Biochemistry
Emma King-Smith, Christian R Zwick, Hans Renata
Nature has evolved a diverse range of oxygenases for the modification of secondary metabolites with selectivity profiles that are unmatched by conventional man-made catalysts. In the past two decades, organic chemists have begun to harness the synthetic potential of these biocatalysts to develop efficient chemoenzymatic synthesis of complex natural products. Judicious combination of synthetic and enzymatic transformations in multi-step synthesis can often result in powerful disconnections that compare favorably with contemporary chemical strategies to access the target natural products, while at the same time, presenting opportunities to innovate...
November 15, 2017: Biochemistry
Alexander E Wilson, Xiaoxue Feng, Nadia N Ono, Doron Holland, Rachel Amir, Li Tian
Galloylated plant specialized metabolites play important roles in plant-environment interactions as well as the promotion of human and animal health. The galloylation reactions are mediated by the formation of galloylglucose esters from gallic acid and UDP-glucose, catalyzed by the plant UGT84 family glycosyltransferases. To explore and exploit the structural determinants of UGT84 activities, we performed homology modeling and substrate docking of PgUGT84A23, a galloylglucose ester-forming family 84 UGT, as well as sequence comparisons of PgUGT84A23 with other functionally characterized plant UGTs...
November 15, 2017: Biochemistry
Robin Roychaudhuri, Tien-Phat V Huynh, Taylor R Whitaker, Elisabeth Hodara, Margaret M Condron, David B Teplow
Amyloid β-protein (Aβ) assembly is a seminal process in Alzheimer's disease. Elucidating the mechanistic features of this process is thought to be vital for the design and targeting of therapeutic agents. Com-putational studies of the most pathologic form of Aβ, the 42-residue Aβ42 peptide, have suggested that hydrogen bonding involving Ser 26 may be particularly important in organizing a monomer folding nucleus and in subse-quent peptide assembly. To study this question, we ex-perimentally determined structure-activity relationships among Aβ42 peptides in which Ser 26 was replaced with Gly, Ala, α-aminobutryic acid (Abu), or Cys...
November 15, 2017: Biochemistry
Yunan Zheng, Raja Mukherjee, Melissa A Chin, Peter Igo, Martin J Gilgenast, Abhishek Chatterjee
Engineered aminoacyl-tRNA synthetase/tRNA pairs that enable site-specific incorporation of noncanonical amino acids (ncAAs) into proteins in living cells have emerged as powerful tools in chemical biology. The Escherichia coli-derived leucyl-tRNA synthetase (EcLeuRS)/tRNA pair is a promising candidate for ncAA mutagenesis in mammalian cells, but it has been engineered to charge only a limited set of ncAAs so far. Here we show that two highly polyspecific EcLeuRS mutants can efficiently charge a large array of useful ncAAs into proteins expressed in mammalian cells, while discriminating against the 20 canonical amino acids...
November 15, 2017: Biochemistry
Abram R Bernard, T Carson Jessop, Prashant Kumar, Nicholas E Dickenson
Type three secretion systems (T3SS) are specialized nano-machines that support infection by injecting bacterial proteins directly into host cells. The Shigella T3SS has uniquely evolved to sense environmental levels of the bile salt deoxycholate (DOC) and up-regulate virulence in response to DOC. In this study, we describe a rare i+5 hydrogen bonding secondary structure element (π-helix) within the type three secretion system tip protein IpaD that plays a critical role in DOC-enhanced virulence. Specifically, engineered mutations within the π-helix altered the pathogen's response to DOC with one mutant construct in particular exhibiting an unprecedented reduction in virulence following DOC exposure...
November 14, 2017: Biochemistry
Wouter Elings, Raffaella Tassoni, Steven A van der Schoot, Wendy Luu, Josef P Kynast, Lin Dai, Anneloes J Blok, Monika Timmer, Bogdan I Florea, Navraj S Pannu, Marcellus Ubbink
The rise of multi- and even totally antibiotic resistant forms of Mycobacterium tuberculosis underlines the need for new antibiotics. The pathogen is resistant to β-lactam compounds due to its native serine β-lactamase, BlaC. This resistance can be circumvented by administration of a β-lactamase inhibitor. We studied the interaction between BlaC and the inhibitor clavulanic acid. Our data show hydrolysis of clavulanic acid and recovery of BlaC activity upon prolonged incubation. The rate of clavulanic acid hydrolysis is much higher in the presence of phosphate ions...
November 14, 2017: Biochemistry
Bryan J Jones, Huey Yee Lim, Jun Huang, Romas J Kazlauskas
A review of the previous stabilization of α/β-hydrolase fold enzymes revealed many different strategies, but no comparison of strategies on the same enzyme. For this reason, we compared five strategies to identify stabilizing mutations in a model α/β-hydrolase fold enzyme, salicylic acid binding protein 2, to reversible denaturation by urea and to irreversible denaturation by heat. The five strategies included one location agnostic approach (random mutagenesis using error-prone polymerase chain reaction), two structure-based approaches [computational design (Rosetta, FoldX) and mutation of flexible regions], and two sequence-based approaches (addition of proline at locations where a more stable homologue has proline and mutation to consensus)...
November 14, 2017: Biochemistry
Nihar Ranjan, Patrick Kellish, Ada King, Dev Priya Arya
Small molecules that modulate biological functions are targets of modern day drug discovery efforts. In a common discovery platform-fragment based drug discovery, two fragments are identified that bind to adjacent sites on a target, and are then linked together using different linkers to identify the linkage for optimum activity. What is not known from these studies is the effects these linkers, that typically contain C, H, and O atoms, have on the properties of the individual fragment. Herein, we investigate such effects in a bisbenzimidazole fragment whose derivatives have a wide range of therapeutic applications in nucleic acid recognition, sensing, photodynamic therapy and as cellular probes...
November 13, 2017: Biochemistry
Teresa Domínguez-Gil, Rafael Molina, David A Dik, Edward Spink, Shahriar Mobashery, Juan A Hermoso
Formation of catenanes by proteins is rare, with few examples known. We report herein the X-ray structure of a catenane dimer of the lytic transglycosylase SltB1 of Pseudomonas aeruginosa. The enzyme is soluble and exists in the periplasmic space, where it modifies bacterial cell wall. The catenane dimer exhibits the protein monomers in a non-covalent chain-link arrangement, whereby a stretch of 51 amino acids (to become a loop and three helices) from one monomer threads through the central opening of the structure of the partner monomer...
November 13, 2017: Biochemistry
Shina Hussain, Diann Andrews, Bruce Charles Hill
The Synthesis of Cytochrome Oxidase protein from Bacillus subtilis (i.e., BsSCO) binds copper with pM affinity, which increases the protein's melting temperature (i.e., TM) by 20 oC. Here two native tryptophans (i.e., W36 and W101) are identified as major contributors to BsSCO's structural form and their contributions to stability, intrinsic fluorescence and copper binding properties of BsSCO are explored. Single mutations of tryptophan to phenylalanine decrease TM by 10 oC and folding free energy by 3-4 kcal/mol...
November 13, 2017: Biochemistry
Rodrigo G Ducati, Ross S Firestone, Vern L Schramm
Plasmodium falciparum parasites are purine auxotrophs that rely exclusively on the salvage of preformed purines from their human hosts to supply the requirement for purine nucleotides. Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) catalyzes the freely reversible Mg2+-dependent conversion of 6-oxopurine bases to their respective nucleotides and inorganic pyrophosphate. The phosphoribosyl group is derived from 5-phospho--D-ribosyl 1-pyrophosphate (PRPP). The enzyme from malaria parasites (PfHGXPRT) is essential as hypoxanthine is the major precursor in purine metabolism...
November 13, 2017: Biochemistry
Patrick H Donnan, Phong Duy Ngo, Steven O Mansoorabadi
The bioluminescence reaction in dinoflagellates involves the oxidation of an open-chain tetrapyrrole by the enzyme dinoflagellate luciferase (LCF). The activity of LCF is tightly regulated by pH, where the enzyme is essentially inactive at pH ~ 8 and optimally active at pH ~ 6. Little is known about the mechanism of LCF and the structure of the active form of the enzyme, although it has been proposed that several intramolecularly conserved histidine residues in the N-terminal region are important for the pH regulation mechanism...
November 13, 2017: Biochemistry
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