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Leibniz Institute for Science and Mathematics Education, Kiel

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  • Articles  (28)
  • 1
    Publication Date: 2018-03-06
    Description: In the face of increasing drug resistance and the rapidly increasing necessity for practicality in clinical settings, drugs targeting different viral proteins are needed in order to control influenza A and B. A small molecule that tenaciously adheres to the PB2cap binding domain, part of the heterotrimeric RNA polymerase machinery of influenza A virus and influenza B virus , is a promising drug candidate. Understanding the anatomic behavior of PB2cap upon ligand binding will aid in the development of a more robust inhibitor. In this report, the anatomic behavior of the influenza A virus PB2cap domain is established by solving the crystal structure of native influenza A virus PB2cap at 1.52 Å resolution. By comparing it with the ligand-bound structure, the dissociation and rotation of the ligand-binding domain in PB2cap from the C-terminal domain is identified. This domain movement is present in many PB2cap structures, suggesting its functional relevance for polymerase activity. A crystallographic structure of native influenza A PB2cap was solved to 1.52 Å resolution. B -factor difference plots and r.m.s.d. plots among known structures suggest functionally relevant disassociation of the N-terminal ligand-binding domain from the C-terminal domain.
    Electronic ISSN: 1744-3091
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Physics
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  • 2
    Publication Date: 2018-03-06
    Description: Pasteurella multocida causes respiratory-tract infections in a broad range of animals, as well as opportunistic infections in humans. P. multocida secretes a multidomain toxin called PfhB2, which contains a YopT-like cysteine protease domain at its C-terminus. The YopT domain of PfhB2 contains a well conserved Cys–His–Asp catalytic triad that defines YopT family members, and shares high sequence similarity with the prototype YopT from Yersinia sp. To date, only one crystal structure of a YopT family member has been reported; however, additional structural information is needed to help characterize the varied substrate specificity and enzymatic action of this large protease family. Here, a catalytically inactive C3733S mutant of PfhB2 YopT that provides enhanced protein stability was used with the aim of gaining structural insight into the diversity within the YopT protein family. To this end, the C3733S mutant of PfhB2 YopT has been successfully cloned, overexpressed, purified and crystallized. Diffraction data sets were collected from native crystals to 3.5 Å resolution and a single-wavelength anomalous data set was collected from an iodide-derivative crystal to 3.2 Å resolution. Data pertaining to crystals belonging to space group P 3 1 , with unit-cell parameters a = 136.9, b = 136.9, c  = 74.7 Å for the native crystals and a  = 139.2, b = 139.2, c = 74.7 Å for the iodide-derivative crystals, are discussed. The crystallization of the YopT-like predicted cysteine protease domain of the secreted toxin PfhB2 from Pasteurella multocida (PfhB2-YopT) is reported. Sequence alignment with structures deposited in the Protein Data Bank indicated no reported homologous structures, suggesting that PfhB2-YopT may represent a novel putative cysteine protease.
    Electronic ISSN: 1744-3091
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Physics
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  • 3
    Publication Date: 2018-03-06
    Description: A recombinant Staphylococcus equorum manganese superoxide dismutase (MnSOD) with an Asp13Arg substitution displays activity over a wide range of pH, at high temperature and in the presence of chaotropic agents, and retains 50% of its activity after irradiation with UVC for up to 45 min. Interestingly, Bacillus subtilis MnSOD does not have the same stability, despite having a closely similar primary structure and thus presumably also tertiary structure. Here, the crystal structure of S. equorum MnSOD at 1.4 Å resolution is reported that may explain these differences. The crystal belonged to space group P 3 2 21, with unit-cell parameters a = 57.36, b = 57.36, c = 105.76 Å, and contained one molecule in the asymmetric unit. The symmetry operation indicates that the enzyme has a dimeric structure, as found in nature and in B. subtilis MnSOD. As expected, their overall structures are nearly identical. However, the loop connecting the helical and α/β domains of S. equorum MnSOD is shorter than that in B. subtilis MnSOD, and adopts a conformation that allows more direct water-mediated hydrogen-bond interactions between the amino-acid side chains of the first and last α-helices in the latter domain. Furthermore, S. equorum MnSOD has a slightly larger buried area compared with the dimer surface area than that in B. subtilis MnSOD, while the residues that form the interaction in the dimer-interface region are highly conserved. Thus, the stability of S. equorum MnSOD may not originate from the dimeric form alone. Furthermore, an additional water molecule was found in the active site. This allows an alternative geometry for the coordination of the Mn atom in the active site of the apo form. This is the first structure of MnSOD from the genus Staphylococcus and may provide a template for the structural study of other MnSODs from this genus. This paper is the first to describe the crystal structure of manganese superoxide dismutase from the genus Staphylococcus . Staphylococcus equorum and Bacillus subtilis MnSODs display different thermal and chemical stabilities. The slightly different structure of S. equorum MnSOD may provide an explanation for the differences in stability.
    Electronic ISSN: 1744-3091
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Physics
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  • 4
    Publication Date: 2018-03-06
    Description: Lens epithelium-derived growth factor (LEDGF)/p75 is the dominant binding partner of HIV-1 integrase in human cells. The crystal structure of the HIV integrase-binding domain (IBD) of LEDGF has been determined in the absence of ligand. IBD was overexpressed in Escherichia coli , purified and crystallized by sitting-drop vapour diffusion. X-ray diffraction data were collected at Diamond Light Source to a resolution of 2.05 Å. The crystals belonged to space group P 2 1 , with eight polypeptide chains in the asymmetric unit arranged as an unusual octamer composed of four domain-swapped IBD dimers. IBD exists as a mixture of monomers and dimers in concentrated solutions, but the dimers are unlikely to be biologically relevant. The HIV integrase-binding domain (IBD) of lens epithelium-derived growth factor has been cloned, purified and crystallized, and its structure has been solved. IBD forms an unusual domain-swapped dimer that assembles into octamers in the crystal.
    Electronic ISSN: 1744-3091
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Physics
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  • 5
    Publication Date: 2018-03-06
    Description: Tight junctions regulate substance permeation through intercellular spaces as a physical barrier or a paracellular pathway, and play an important role in maintaining the internal environment. Claudins, which are tetraspan-transmembrane proteins, are pivotal components of tight junctions. In mammals 27 claudin subtypes have been identified, each of which interacts with specific subtypes. Although the crystal structures of several subtypes have been determined, the molecular mechanisms underlying subtype specificity remain unclear. Here, mouse claudin-3 (mCldn3) was crystallized in complex with the C-terminal region of Clostridium perfringens enterotoxin (C-CPE) for the structural analysis of an additional claudin subtype. mCldn3 alone was difficult to crystallize, but complex formation with C-CPE enhanced the thermostability of mCldn3 and facilitated its crystallization. The introduction of an S313A mutation into C-CPE further improved its thermostability, and the resolution limits of the diffraction data sets improved from 8 Å for the wild-type complex to 4.7 Å for the S313A mutant complex. Mouse claudin-3 was crystallized in complex with the carboxyl-terminal region of C. perfringens enterotoxin and a data set was collected to 4.2 Å resolution.
    Electronic ISSN: 1744-3091
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Physics
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  • 6
    Publication Date: 2018-03-06
    Description: Mitogen-activated protein kinase (MAPK)-interacting kinases 1 (Mnk1) and 2 (Mnk2) modulate translation initiation through the phosphorylation of eukaryotic translation initiation factor 4E, which promotes tumorigenesis. However, Mnk1 and Mnk2 are dispensable in normal cells, suggesting that the inhibition of Mnk1 and Mnk2 could be effective in cancer therapy. To provide a structural basis for Mnk1 inhibition, a novel Mnk1 inhibitor was discovered and the crystal structure of Mnk1 in complex with this inhibitor was determined. The crystal structure revealed that the inhibitor binds to the autoinhibited state of Mnk1, stabilizing the Mnk-specific DFD motif in the DFD-out conformation, thus preventing Mnk1 from switching to the active conformation and thereby inhibiting the kinase activity. These results provide a valuable platform for the structure-guided design of Mnk1 inhibitors. The structure of MAPK-interacting kinase 1 (Mnk1) in complex with a novel Mnk1-selective inhibitor was determined. It was found that the inhibitor stabilizes the auto-inhibited inactive state of Mnk1.
    Electronic ISSN: 1744-3091
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Physics
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  • 7
    Publication Date: 2018-03-06
    Description: Tuberculosis (TB) continues to remain a leading cause of death globally. Of particular concern is the emergence and rise in incidence of multidrug-resistant and extremely drug-resistant cases of TB. To counter this threat, it is important to explore alternative therapies, including phage therapy. Phage BTCU-1 specifically infects Mycobacterium spp. and kills the majority of them. Intriguingly, many proteins from the phage do not share high amino-acid sequence identity with proteins from species other than phages. Here, the expression, purification and crystallization of one such protein, a putative phosphoribosyl transferase from phage BTCU-1, is reported. The crystals belonged to space group C 222 1 , with unit-cell parameters a = 59.71, b = 64.42, c  = 65.32 Å, α = β = γ = 90°. The crystals diffracted X-rays to 2.2 Å resolution. A putative phosphoribosyl transferase from phage BTCU-1 that infects Mycobacterium and shows no sequence similarity to any structure deposited in the Protein Data Bank was cloned, expressed, purified and crystallized. The crystals diffracted X-rays to 2.2 Å resolution.
    Electronic ISSN: 1744-3091
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Physics
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  • 8
    Publication Date: 2018-03-06
    Description: The MSMEG_4306 gene from Mycobacterium smegmatis encodes a protein of unknown function with 242 amino-acid residues that contains a conserved zinc-ribbon domain at its C-terminus. Here, the crystal structure of MSMEG_4306 determined by the single-wavelength anomalous dispersion method using just one zinc ion co-purified with the protein is reported. The crystal structure of MSMEG_4306 shows a coiled-coil helix domain in the N-terminal region and a zinc-ribbon domain in the C-terminal region. A structural similarity search against the Protein Data Bank using MSMEG_4306 as a query revealed two similar structures, namely CT398 from Chlamydia trachomatis and HP0958 from Helicobacter pylori , although they share only ∼15% sequence identity with MSMEG_4306. Based on comparative analysis, it is predicted that MSMEG_4306 may be involved in secretion systems, possibly by interacting with multiple proteins or nucleic acids. This article reports the crystal structure of MSMEG_4306, a hypothetical protein from Mycobacterium smegmatis , determined by zinc SAD phasing.
    Electronic ISSN: 1744-3091
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Physics
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  • 9
    Publication Date: 2018-03-06
    Description: NS1-binding protein (NS1-BP), which belongs to the Kelch protein superfamily, was first identified as a novel human 70 kDa protein that interacts with NS1 of Influenza A virus . It is involved in many cell functions, including pre-mRNA splicing, the ERK signalling pathway, the aryl hydrocarbon receptor (AHR) pathway, F-actin organization and protein ubiquitylation. However, the structure of NS1-BP is still unknown, which may impede functional studies. Here, the structure of the C-terminal Kelch domain of NS1-BP (NS1-BP-C; residues 330–642) was determined at 1.98 Å resolution. The Kelch domain adopts a highly symmetric six-bladed β-propeller fold structure. Each blade of the β-propeller is composed of four antiparallel β-strands. Comparison of the Kelch-domain structures of NS1-BP and its homologues showed that the Gly–Gly pair in β-strand B and the hydrophobic Trp residue in β-strand D are highly conserved, while the B – C loops in blades 2 and 6 are variable. This structure of the Kelch domain of NS1-BP extends the understanding of NS1-BP. NS1-binding protein (NS1-BP) is involved in many cell functions, including pre-mRNA splicing, the ERK signalling pathway, the aryl hydrocarbon receptor pathway, F-actin organization and protein ubiquitylation. Here, the structure of the C-terminal Kelch domain of NS1-BP is reported at 1.98 Å resolution.
    Electronic ISSN: 1744-3091
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Physics
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  • 10
    Publication Date: 2018-03-06
    Description: Pyruvate decarboxylase (PDC; EC 4.1.1.1) is a key enzyme in homofermentative metabolism where ethanol is the major product. PDCs are thiamine pyrophosphate- and Mg 2+ ion-dependent enzymes that catalyse the non-oxidative decarboxylation of pyruvate to acetaldehyde and carbon dioxide. As this enzyme class is rare in bacteria, current knowledge of bacterial PDCs is extremely limited. One approach to further the understanding of bacterial PDCs is to exploit the diversity provided by evolution. Ancestral sequence reconstruction (ASR) is a method of computational molecular evolution to infer extinct ancestral protein sequences, which can then be synthesized and experimentally characterized. Through ASR a novel PDC was generated, designated ANC27, that shares only 78% amino-acid sequence identity with its closest extant homologue ( Komagataeibacter medellinensis PDC, GenBank accession No. WP_014105323.1), yet is fully functional. Crystals of this PDC diffracted to 3.5 Å resolution. The data were merged in space group P 3 2 21, with unit-cell parameters a = b = 108.33, c = 322.65 Å, and contained two dimers (two tetramer halves) in the asymmetric unit. The structure was solved by molecular replacement using PDB entry 2wvg as a model, and the final R values were R work = 0.246 (0.3671 in the highest resolution bin) and R free = 0.319 (0.4482 in the highest resolution bin). Comparison with extant bacterial PDCs supports the previously observed correlation between decreased tetramer interface area (and number of interactions) and decreased thermostability. An ancestral bacterial pyruvate decarboxylase (with an inferred age of 1248 million years) was reconstructed through ancestral sequence reconstruction, synthesized and recombinantly expressed in E. coli . The enzyme is fully functional and its crystal structure was elucidated to 3.5 Å resolution.
    Electronic ISSN: 1744-3091
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Physics
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