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  • 1
    Language: English
    In: Virus Research, March 2013, Vol.172(1-2), pp.75-80
    Description: Influenza A virus is an important human pathogen accounting for widespread morbidity and mortality, with new strains emerging from animal reservoirs possessing the potential to cause pandemics. The influenza A RNA-dependent RNA polymerase complex consists of three subunits (PA, PB1, and PB2) and catalyzes viral RNA replication and transcription activities in the nuclei of infected host cells. The PB2 subunit has been implicated in pathogenicity and host adaptation. This includes the inhibition of type I interferon induction through interaction with the host's mitochondrial antiviral signaling protein (MAVS), an adaptor molecule of RIG-I-like helicases. This study reports the identification of the cognate PB2 and MAVS interaction domains necessary for complex formation. Specifically, MAVS residues 1–150, containing both the CARD domain and the N-terminal portion of the proline rich-region, and PB2 residues 1–37 are essential for PB2–MAVS virus–host protein–protein complex formation. The three α-helices constituting PB2 (1–37) were tested to determine their relative influence in complex formation, and Helix3 was observed to promote the primary interaction with MAVS. The PB2 MAVS-binding domain unexpectedly coincided with its PB1-binding domain, indicating an important dual functionality for this region of PB2. Analysis of these interaction domains suggests both virus and host properties that may contribute to host tropism. Additionally, the results of this study suggest a new strategy to develop influenza A therapeutics by simultaneously blocking PB2–MAVS and PB2–PB1 protein–protein interactions and their resulting activities.
    Keywords: Influenza A Virus ; Polymerase Subunit Pb2 ; Polymerase Subunit Pb1 ; Mitochondrial Antiviral Signaling Protein (Mavs) ; Protein–Protein Interaction (Ppi) ; Host Tropism ; Biology
    ISSN: 0168-1702
    E-ISSN: 1872-7492
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 01 February 2005, Vol.102(5), pp.1378-83
    Description: The luciferase of Lingulodinium polyedrum, a marine bioluminescent dinoflagellate, consists of three similar but not identical domains in a single polypeptide. Each encodes an active luciferase that catalyzes the oxidation of a chlorophyll-derived open tetrapyrrole (dinoflagellate luciferin) to produce blue light. These domains share no sequence similarity with any other in the GenBank database and no structural or motif similarity with any other luciferase. We report here the 1.8-A crystal structure of the third domain, D3, at pH 8, and a mechanism for its activity regulation by pH. D3 consists of two major structural elements: a beta-barrel pocket putatively for substrate binding and catalysis and a regulatory three-helix bundle. N-terminal histidine residues previously shown to regulate activity by pH are at the interface of the helices in the bundle. Molecular dynamics calculations indicate that, in response to changes in pH, these histidines could trigger a large molecular motion of the bundle, thereby exposing the active site to the substrate.
    Keywords: Dinoflagellida -- Enzymology ; Luciferases -- Genetics ; Luminescent Proteins -- Genetics ; Tetrapyrroles -- Metabolism
    ISSN: 0027-8424
    E-ISSN: 10916490
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  • 3
    Language: English
    In: Future microbiology, 2014, Vol.9(10), pp.1113-6
    Description: [...]avibactam, a non-β-lactam β-lactamase inhibitor, delivered in combination with ceftazadime was the only novel anti-GNB in clinical trials. [...]many major pharmaceutical companies have exited antimicrobial R&D. In order to address the dearth of antibiotic development, in 2012 the Generating Antibiotic...
    Keywords: Acinetobacter Baumannii ; Gram-Negative Bacilli ; Antibiotic Target ; Bacterial Drug Target ; Essential Genes ; Multidrug Resistant ; Drug Resistance, Multiple, Bacterial ; Anti-Infective Agents -- Isolation & Purification ; Drug Discovery -- Methods ; Gram-Negative Bacteria -- Drug Effects
    ISSN: 17460913
    E-ISSN: 1746-0921
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  • 4
    In: Biochemistry, April 24, 2001, Vol.40(16), p.4949(8)
    Description: His12 and His119 appear to be necessary for ribonuclease A to bind nucleic acids. Although their substitution with other amino acids does not affect the structure of the enzyme, the histidines contribute 1.4 and 1.1 kcal/mol, respectively, to the stability of the enzyme.
    Keywords: Ribonuclease -- Research ; Enzyme Structure-activity Relationships
    ISSN: 0006-2960
    E-ISSN: 15204995
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  • 5
    In: Infection and Immunity, 2010, Vol. 78(9), p.3993
    Description: Acinetobacter baumannii is a pathogen of increasing medical importance with a propensity to be multidrug resistant, thereby making treatment challenging. Little is known of virulence traits in A. baumannii. To identify virulence factors and potential drug targets, random transposon (Tn) mutants derived from the A. baumannii strain AB307-0294 were screened to identify genes essential for growth in human ascites fluid in vitro, an inflammatory exudative fluid. These studies led to the identification of two genes that were predicted to be required for capsule polymerization and assembly. The first, ptk, encodes a putative protein tyrosine kinase (PTK), and the second, epsA, encodes a putative polysaccharide export outer membrane protein (EpsA). Monoclonal antibodies used in flow cytometric and Western analyses confirmed that these genes are required for a capsule-positive phenotype. A capsule-positive phenotype significantly optimized growth in human ascites fluid, survival in human serum, and survival in a rat soft tissue infection model. Importantly, the clearance of the capsule-minus mutants AB307.30 (ptk mutant, capsule minus) and AB307.45 (epsA mutant, capsule minus) was complete and durable. These data demonstrated that the K1 capsule from AB307-0294 was an important protectin. Further, these data suggested that conserved proteins, which contribute to the capsule-positive phenotype, are potential antivirulence drug targets. Therefore, the results from this study have important biologic and translational implications and, to the best of our knowledge, are the first to address the role of capsule in the pathogenesis of A. baumannii infection.
    Keywords: Translation ; Outer Membrane Proteins ; Data Processing ; Polymerization ; Virulence Factors ; Monoclonal Antibodies ; Animal Models ; Survival ; Medical Importance ; Pathogens ; Infection ; Inflammation ; Flow Cytometry ; Transposons ; Ascites ; Protein-Tyrosine Kinase ; Multidrug Resistance ; Soft Tissues ; Capsular Polysaccharides ; Drugs ; Acinetobacter Baumannii ; Microorganisms & Parasites ; Immunology;
    ISSN: 0019-9567
    ISSN: 00199567
    E-ISSN: 10985522
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  • 6
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 01 September 1998, Vol.95(18), pp.10407-10412
    Description: Select members of the bovine pancreatic ribonuclease A (RNase A) superfamily are potent cytotoxins. These cytotoxic ribonucleases enter the cytosol, where they degrade cellular RNA and cause cell death. Ribonuclease inhibitor (RI), a cytosolic protein, binds to members of the RNase A superfamily with inhibition constants that span 10 orders of magnitude. Here, we show that the affinity of a ribonuclease for RI plays an integral role in defining the potency of a cytotoxic ribonuclease. RNase A is not cytotoxic and binds RI with high affinity. Onconase, a cytotoxic RNase A homolog, binds RI with low affinity. To disrupt the RI-RNase A interaction, three RNase A residues (Asp-38, Gly-88, and Ala-109) that form multiple contacts with RI were replaced with arginine. Replacing Asp-38 and Ala-109 with an arginine residue has no effect on the RI-RNase interaction. In addition, these variants are not cytotoxic. In contrast, replacing Gly-88 with an arginine residue yields a ribonuclease (G88R RNase A) that retains catalytic activity in the presence of RI and is cytotoxic to a transformed cell line. Replacing Gly-88 with aspartate also yields a ribonuclease (G88D RNase A) with a decreased affinity for RI and cytotoxic activity. The cytotoxic potency of onconase, G88R RNase A, and G88D RNase A correlate with RI evasion. We conclude that ribonucleases that retain catalytic activity in the presence of RI are cytotoxins. This finding portends the development of a class of chemotherapeutic agents based on pancreatic ribonucleases.
    Keywords: Health sciences -- Health and wellness -- Public health ; Biological sciences -- Biochemistry -- Chemical compounds ; Physical sciences -- Chemistry -- Chemical compounds ; Physical sciences -- Chemistry -- Chemical compounds ; Physical sciences -- Chemistry -- Material properties ; Applied sciences -- Materials science -- Chemical compounds ; Physical sciences -- Chemistry -- Cytology ; Biological sciences -- Biology -- Chemical compounds ; Physical sciences -- Chemistry -- Zoology ; Biological sciences -- Biology -- Zoology
    ISSN: 00278424
    E-ISSN: 10916490
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  • 7
    In: Journal of the American Chemical Society, April 6, 1994, Vol.116(7), p.3129(2)
    Description: X-ray diffraction techniques determine the three-dimensional structure and architecture of FKBP13. FKBP13 is made up of a four-stranded beta sheet surrounded by a short seven-residue alpha helix. The protein structure of FKBP13 causes poor calcineurinization.
    Keywords: Active Sites (Biochemistry) -- Research ; Protein Structure
    ISSN: 0002-7863
    E-ISSN: 15205126
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  • 8
    In: Biochemistry, June 23, 1998, Vol.37(25), p.8886(13)
    Description: A study of the function and importance of the aspartate residue in the catalytic dyad of ribonuclease A (RNase A) is presented. RNase A catalyzes the hydrolysis of the P-O(super 5') bond of RNA on the 3' side of pyrimidine residues. RNase A mutants have been synthesized in which Asp121 can be replaced with a asparagine or alanine residue. Results that there is no change in the structure of RNase A when Asp121 is subsituted with an asparagine or alanine residue. However, the rate of transphosphorylation decreased by 100 fold and the rate of hydrolysis decreased by 10 fold.
    Keywords: Ribonuclease -- Analysis ; Serine -- Analysis ; Proteases -- Analysis
    ISSN: 0006-2960
    E-ISSN: 1943295X
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  • 9
    In: Biochemistry, Dec 15, 1998, Vol.37(50), p.17386(1)
    Description: The effect of long-range Coulombic interactions on the active site of bovine pancreatic ribonuclease A was investigated using X-ray diffraction analyses. in addition, the structure of K7A/R10A/K66A ribonuclease A was characterized. The importance of the residues beyond RNA binding was also established using (super 1)H nuclear magnetic resonance spectroscopy, steady-state kinetics and isothermal titration calorimetry. Experimental results showed that long-range Coulombic forces play a critical role in the catalysis of RNA cleavage by ribonuclease A.
    Keywords: Ribonuclease -- Research ; Active Sites (Biochemistry) -- Research ; Rna -- Research ; Enzymes -- Research ; Catalysis -- Research ; Scission (Chemistry) -- Research
    ISSN: 0006-2960
    E-ISSN: 15204995
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  • 10
    In: Acta Crystallographica Section D, 01 August 2015, Vol.71(8), pp.1736-1744
    Description: is an opportunistic Gram‐negative pathogen that is an important cause of healthcare‐associated infections exhibiting high mortality rates. Clinical isolates of multidrug‐resistant (MDR) and extremely drug‐resistant (XDR) strains are increasingly being observed. Compounding this concern is the dearth of new antibacterial agents in late‐stage development that are effective against MDR and XDR . As part of an effort to address these concerns, two genes ( and ) of the shikimate pathway have previously been determined to be essential for the growth and survival of during host infection ( to be essential ). This study expands upon these results by demonstrating that the gene, encoding shikimate kinase (SK), is also essential in a rat soft‐tissue infection model. The crystal structure of SK in complex with the substrate shikimate and a sulfate ion that mimics the binding interactions expected for the β‐phosphate of ATP was then determined to 1.91 Å resolution and the enzyme kinetics were characterized. The flexible shikimate‐binding domain and LID region are compared with the analogous regions in other SK crystal structures. The impact of structural differences and sequence divergence between SKs from pathogenic bacteria that may influence antibiotic‐development efforts is discussed.
    Keywords: Shikimate Kinase ; Acinetobacter Baumannii ; Essential Gene ; Antibiotic Target ; Multi‐Drug And Extreme Drug Resistance ; Ligand‐Induced Conformational Change ; Enzyme Kinetics
    ISSN: 1399-0047
    ISSN: 09074449
    E-ISSN: 1399-0047
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