References of "Damblon, Christian"
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See detailStructural and functional analysis of the HMA4 protein
Lekeux, Gilles ULg; Laurent, Clémentine ULg; Damblon, Christian ULg et al

Poster (2014, September 09)

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See detailA variety of roles for versatile zinc in metallo-b-lactamases
Karsisiotis, Andreas Ioannis; Damblon, Christian ULg; Roberts, Gordon C K

in Metallomics (2014)

Metallo-b-lactamases are important as a major source of resistance of pathogenic bacteria to the widely used b-lactam antibiotics. They show considerable diversity in terms of sequence and are grouped ... [more ▼]

Metallo-b-lactamases are important as a major source of resistance of pathogenic bacteria to the widely used b-lactam antibiotics. They show considerable diversity in terms of sequence and are grouped into three subclasses, B1, B2 and B3, which share a common overall fold. In each case the active enzyme has binding sites for two zinc ions in close proximity, although the amino-acid residues which coordinate the metals vary from one subclass to another. In subclasses B1 and B3, there has been controversy about whether both zinc ions are required for activity, but the most recent evidence indicates that there is positive cooperativity in zinc binding and that the catalytically relevant species is the di-zinc enzyme. Subclass B2 enzymes, on the other hand, are active in the mono-zinc state and are inhibited by the binding of a second zinc ion. Evidence for the importance of the zinc ions in substrate binding has come from structures of product complexes which indicate that the b-lactam core binds to subclass B1 and B3 enzymes in a rather consistent fashion, interactions with the zinc ions being centrally important. The zinc ions play key roles in the catalytic mechanism, including facilitating nucleophilic attack on the amide carbonyl by the zinc-bound hydroxide ion, stabilising the anionic tetrahedral intermediate and coordinating the departing amine nitrogen. [less ▲]

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See detailComplete 1H, 15N and 13C resonance assignments of Bacillus cereus metallo-b-lactamase and its complex with the inhibitor R-thiomandelic acid
Karsisiotis, Andreas Ioannis; Damblon, Christian ULg; Roberts, Gordon C K

in Biomolecular NMR Assignments (2014), 8

b-Lactamases inactivate b-lactam antibiotics by hydrolysis of their endocyclic b-lactam bond and are a major cause of antibiotic resistance in pathogenic bacteria. The zinc dependent metallo-b-lactamase ... [more ▼]

b-Lactamases inactivate b-lactam antibiotics by hydrolysis of their endocyclic b-lactam bond and are a major cause of antibiotic resistance in pathogenic bacteria. The zinc dependent metallo-b-lactamase enzymes are of particular concern since they are located on highly transmissible plasmids and have a broad spectrum of activity against almost all b-lactam antibiotics. We present here essentially complete ([96 %) backbone and sidechain sequence-specific NMR resonance assignments for the Bacillus cereus subclass B1 metallo-b-lactamase, BcII, and for its complex with R-thiomandelic acid, a broad spectrum inhibitor of metallo-b-lactamases. These assignments have been used as the basis for determination of the solution structures of the enzyme and its inhibitor complex and can also be used in a rapid screen for other metallo-b-lactamase inhibitors. [less ▲]

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See detailSynthesis and biological evaluation of potential threonine synthase inhibitors: Rhizocticin A and Plumbemycin A
Gahungu; Arguelles Arias, Anthony ULg; Fickers, Patrick ULg et al

in Bioorganic & Medicinal Chemistry (2013), 21

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See detailSolution structures of the Bacillus cereus metallo-β-lactamase BcII and its complex with the broad spectrum inhibitor R-thiomandelic acid
Karsisiotis, Andreas Ioannis; Damblon, Christian ULg; Roberts, Gordon C K

in Biochemical Journal (2013), 456

Metallo-β-lactamases, enzymes which inactivate β-lactam antibiotics, are of increasing biological and clinical significance as a source of antibiotic resistance in pathogenic bacteria. In the present ... [more ▼]

Metallo-β-lactamases, enzymes which inactivate β-lactam antibiotics, are of increasing biological and clinical significance as a source of antibiotic resistance in pathogenic bacteria. In the present study we describe the high-resolution solution NMR structures of the Bacillus cereus metallo-β-lactamase BcII and of its complex with R-thiomandelic acid, a broadspectrum inhibitor of metallo-β-lactamases. This is the first reported solution structure of any metallo-β-lactamase. There are differences between the solution structure of the free enzyme and previously reported crystal structures in the loops flanking the active site, which are important for substrate and inhibitor binding and catalysis. The binding of R-thiomandelic acid and the roles of active-site residues are defined in detail. Changes in the enzyme structure upon inhibitor binding clarify the role of the mobile β3–β4 loop. Comparisons with other metallo-β- lactamases highlight the roles of individual amino-acid residues in the active site and the β3–β4 loop in inhibitor binding and provide information on the basis of structure–activity relationships among metallo-β-lactamase inhibitors. [less ▲]

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See detailSynthesis and biological evaluation of potential threonine synthase inhibitors: Rhizocticin A and Plumbemycin A.
Gahungu, Mathias; Arguelles-Arias, Anthony; Fickers, Patrick et al

in Bioorganic & Medicinal Chemistry (2013), 21(17), 4958-67

Rhizocticins and Plumbemycins are natural phosphonate antibiotics produced by the bacterial strains Bacillus subtilis ATCC 6633 and Streptomyces plumbeus, respectively. Up to now, these potential ... [more ▼]

Rhizocticins and Plumbemycins are natural phosphonate antibiotics produced by the bacterial strains Bacillus subtilis ATCC 6633 and Streptomyces plumbeus, respectively. Up to now, these potential threonine synthase inhibitors have only been synthesized under enzymatic catalysis. Here we report the chemical stereoselective synthesis of the non-proteinogenic (S,Z)-2-amino-5-phosphonopent-3-enoic acid [(S,Z)-APPA] and its use for the synthesis of Rhizocticin A and Plumbemycin A. In this work, (S,Z)-APPA was synthesized via the Still-Gennari olefination starting from Garner's aldehyde. The Michaelis-Arbuzov reaction was used to form the phosphorus-carbon bond. Oligopeptides were prepared using liquid phase peptide synthesis (LPPS) and were tested against selected bacteria and fungi. [less ▲]

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See detailLigand Binding Study of Human PEBP1/RKIP: Interaction with Nucleotides and Raf-1 Peptides Evidenced by NMR and Mass Spectrometry
Tavel, Laurette ULg; Jaquillard, Lucie; Karsisiotis, Andreas et al

in PLoS ONE (2012), 7(4): e36187

Background Human Phosphatidylethanolamine binding protein 1 (hPEBP1) also known as Raf kinase inhibitory protein (RKIP), affects various cellular processes, and is implicated in metastasis formation and ... [more ▼]

Background Human Phosphatidylethanolamine binding protein 1 (hPEBP1) also known as Raf kinase inhibitory protein (RKIP), affects various cellular processes, and is implicated in metastasis formation and Alzheimer's disease. Human PEBP1 has also been shown to inhibit the Raf/MEK/ERK pathway. Numerous reports concern various mammalian PEBP1 binding ligands. However, since PEBP1 proteins from many different species were investigated, drawing general conclusions regarding human PEBP1 binding properties is rather difficult. Moreover, the binding site of Raf-1 on hPEBP1 is still unknown. Methods/Findings In the present study, we investigated human PEBP1 by NMR to determine the binding site of four different ligands: GTP, FMN, and one Raf-1 peptide in tri-phosphorylated and non-phosphorylated forms. The study was carried out by NMR in near physiological conditions, allowing for the identification of the binding site and the determination of the affinity constants KD for different ligands. Native mass spectrometry was used as an alternative method for measuring KD values. Conclusions/Significance Our study demonstrates and/or confirms the binding of hPEBP1 to the four studied ligands. All of them bind to the same region centered on the conserved ligand-binding pocket of hPEBP1. Although the affinities for GTP and FMN decrease as pH, salt concentration and temperature increase from pH 6.5/NaCl 0 mM/20°C to pH 7.5/NaCl 100 mM/30°C, both ligands clearly do bind under conditions similar to what is found in cells regarding pH, salt concentration and temperature. In addition, our work confirms that residues in the vicinity of the pocket rather than those within the pocket seem to be required for interaction with Raf-1. [less ▲]

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See detailEfficient determination of diffusion coefficients by monitoring transport during recovery delays in NMR
Augustyniak, Rafal; Ferrage, Fabien; Damblon, Christian ULg et al

in Chemical Communications (2012), 48

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See detailAn alternative flexible conformation of the E. coli HUbeta(2) protein: structural, dynamics, and functional aspects.
Garnier, N.; Loth, K.; Coste, F. et al

in European Biophysics Journal [=EBJ] (2011), 40(2), 117-129

The histone-like HU protein is the major nucleoid-associated protein involved in the dynamics and structure of the bacterial chromosome. Under physiological conditions, the three possible dimeric forms of ... [more ▼]

The histone-like HU protein is the major nucleoid-associated protein involved in the dynamics and structure of the bacterial chromosome. Under physiological conditions, the three possible dimeric forms of the E. coli HU protein (EcHUalpha(2), EcHUbeta(2), and EcHUalphabeta) are in thermal equilibrium between two dimeric conformations (N(2) <--> I(2)) varying in their secondary structure content. High-temperature molecular dynamics simulations combined with NMR experiments provide information about structural and dynamics features at the atomic level for the N(2) to I(2) thermal transition of the EcHUbeta(2) homodimer. On the basis of these data, a realistic 3D model is proposed for the major I(2) conformation of EcHUbeta(2). This model is in agreement with previous experimental data. [less ▲]

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See detail1H, 13C and 15N backbone resonance assignments for the BS3 class A beta-lactamase from Bacillus licheniformis.
Vandenameele, Julie ULg; Matagne, André ULg; Damblon, Christian ULg

in Biomolecular NMR Assignments (2010), 4(2), 195-7

Class A beta-lactamases (260-280 amino acids; M ( r ) ~ 29,000) are among the largest proteins studied in term of their folding properties. They are composed of two structural domains: an all-alpha domain ... [more ▼]

Class A beta-lactamases (260-280 amino acids; M ( r ) ~ 29,000) are among the largest proteins studied in term of their folding properties. They are composed of two structural domains: an all-alpha domain formed by five to eight helices and an alpha/beta domain consisting of a five-stranded antiparallel beta-sheet covered by three to four alpha-helices. The alpha domain (~150 residues) is made up of the central part of the polypeptide chain whereas the alpha/beta domain (111-135 residues) is constituted by the N- and C-termini of the protein. Our goal is to determine in which order the different secondary structure elements are formed during the folding of BS3. With this aim, we will use pulse-labelling hydrogen/deuterium exchange experiments, in combination with 2D-NMR measurements, to monitor the time-course of formation and stabilization of secondary structure elements. Here we report the backbone resonance assignments as the requirement for further hydrogen/deuterium exchange studies. [less ▲]

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See detailNMR structure of a phosphatidylethanolamine binding protein from Drosophila
Rautureau, Gilles J P; Vovelle, Francoise; Schoentgen, Francoise et al

in Proteins (2010), 78(6), 1606-1610

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See detailHigh-level biosynthesis of the anteiso-C(17) isoform of the antibiotic mycosubtilin in Bacillus subtilis and characterization of its candidacidal activity.
Fickers, Patrick ULg; Guez, Jean-Sebastien; Damblon, Christian ULg et al

in Applied and Environmental Microbiology (2009), 75(13), 4636-40

High-level production (880 mg liter(-1)) and isolation of the anteiso-C(17) isoform of the lipopeptide mycosubtilin produced by a genetically engineered Bacillus subtilis strain are reported. Antifungal ... [more ▼]

High-level production (880 mg liter(-1)) and isolation of the anteiso-C(17) isoform of the lipopeptide mycosubtilin produced by a genetically engineered Bacillus subtilis strain are reported. Antifungal activity of this isoform, as determined via culture and fluorometric and cell leakage assays, suggests its potential therapeutic use as an antifungal agent, in particular against Candida spp. [less ▲]

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