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  • 1
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2024
    In:  Current Opinion in Nephrology & Hypertension Vol. 33, No. 4 ( 2024-07), p. 447-455
    In: Current Opinion in Nephrology & Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 33, No. 4 ( 2024-07), p. 447-455
    Abstract: More than a decade ago, apolipoprotein L1 ( APOL1 ) risk alleles designated G1 and G2, were discovered to be causally associated with markedly increased risk for progressive kidney disease in individuals of recent African ancestry. Gratifying progress has been made during the intervening years, extending to the development and clinical testing of genomically precise small molecule therapy accompanied by emergence of RNA medicine platforms and clinical testing within just over a decade. Recent findings Given the plethora of excellent prior review articles, we will focus on new findings regarding unresolved questions relating mechanism of cell injury with mode of inheritance, regulation and modulation of APOL1 activity, modifiers and triggers for APOL1 kidney risk penetrance, the pleiotropic spectrum of APOL1 related disease beyond the kidney – all within the context of relevance to therapeutic advances. Summary Notwithstanding remaining controversies and uncertainties, promising genomically precise therapies targeted at APOL1 mRNA using antisense oligonucleotides (ASO), inhibitors of APOL1 expression, and small molecules that specifically bind and inhibit APOL1 cation flux are emerging, many already at the clinical trial stage. These therapies hold great promise for mitigating APOL1 kidney injury and possibly other systemic phenotypes as well. A challenge will be to develop guidelines for appropriate use in susceptible individuals who will derive the greatest benefit.
    Type of Medium: Online Resource
    ISSN: 1062-4821 , 1473-6543
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2024
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  • 2
    Online Resource
    Online Resource
    American Association for the Advancement of Science (AAAS) ; 2017
    In:  Science Vol. 355, No. 6327 ( 2017-02-24), p. 831-833
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 355, No. 6327 ( 2017-02-24), p. 831-833
    Abstract: Amyloids are ordered protein aggregates, found in all kingdoms of life, and are involved in aggregation diseases as well as in physiological activities. In microbes, functional amyloids are often key virulence determinants, yet the structural basis for their activity remains elusive. We determined the fibril structure and function of the highly toxic, 22-residue phenol-soluble modulin α3 (PSMα3) peptide secreted by Staphylococcus aureus . PSMα3 formed elongated fibrils that shared the morphological and tinctorial characteristics of canonical cross-β eukaryotic amyloids. However, the crystal structure of full-length PSMα3, solved de novo at 1.45 angstrom resolution, revealed a distinctive “cross-α” amyloid-like architecture, in which amphipathic α helices stacked perpendicular to the fibril axis into tight self-associating sheets. The cross-α fibrillation of PSMα3 facilitated cytotoxicity, suggesting that this assembly mode underlies function in S. aureus .
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    RVK:
    RVK:
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2017
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    SSG: 11
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  • 3
    Online Resource
    Online Resource
    International Union of Crystallography (IUCr) ; 2013
    In:  Acta Crystallographica Section F Structural Biology and Crystallization Communications Vol. 69, No. 10 ( 2013-10-01), p. 1114-1119
    In: Acta Crystallographica Section F Structural Biology and Crystallization Communications, International Union of Crystallography (IUCr), Vol. 69, No. 10 ( 2013-10-01), p. 1114-1119
    Type of Medium: Online Resource
    ISSN: 1744-3091
    Language: Unknown
    Publisher: International Union of Crystallography (IUCr)
    Publication Date: 2013
    detail.hit.zdb_id: 2175956-X
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  • 4
    Online Resource
    Online Resource
    Wiley ; 2013
    In:  The FEBS Journal Vol. 280, No. 3 ( 2013-02), p. 950-964
    In: The FEBS Journal, Wiley, Vol. 280, No. 3 ( 2013-02), p. 950-964
    Abstract: Type I galactan is a pectic polysaccharide composed of β‐1,4 linked units of d ‐galactose and is part of the main plant cell wall polysaccharides, which are the most abundant sources of renewable carbon in the biosphere. The thermophilic bacterium G eobacillus stearothermophilus T‐6 possesses an extensive system for the utilization of plant cell wall polysaccharides, including a 9.4‐kb gene cluster, ganREFGBA , which encodes galactan‐utilization elements. Based on enzyme activity assays, the ganEFGBA genes, which probably constitute an operon, are induced by short galactosaccharides but not by galactose. Gan A is a glycoside hydrolase family 53 β‐1,4‐galactanase, active on high molecular weight galactan, producing galactotetraose as the main product. Homology modelling of the active site residues suggests that the enzyme can accommodate at least eight galactose molecules (at subsites −4 to +4) in the active site. G an B is a glycoside hydrolase family 42 β‐galactosidase capable of hydrolyzing short β‐1,4 galactosaccharides into galactose. Applying both Gan A and Gan B on galactan resulted in the full degradation of the polymer into galactose. The ganEFG genes encode an ATP ‐binding cassette sugar transport system whose sugar‐binding lipoprotein, G an E , was shown to bind galacto‐oligosaccharides. The utilization of galactan by G . stearothermophilus involves the extracellular galactanase G an A cleaving galactan into galacto‐oligosaccharides that enter the cell via a specific transport system G an EFG . The galacto‐oligosaccharides are further degraded by the intracellular β‐galactosidase G an B into galactose, which is then metabolized into UDP ‐glucose via the Leloir pathway by the galKET gene products. Database Nucleotide sequence data have been deposited in the GenBank database under the accession number JF327803 .
    Type of Medium: Online Resource
    ISSN: 1742-464X , 1742-4658
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2013
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    SSG: 12
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  • 5
    In: FEBS Letters, Wiley, Vol. 586, No. 16 ( 2012-07-30), p. 2436-2442
    Abstract: ► The abp gene from G. stearothermophilus encodes for a family 27 arabinopyranosidase. ► By using 13 C NMR the removal of arabinopyranoside from galactan was demonstrated. ► A single residue, Ile 67 in Abp, appears to control substrate specificity.
    Type of Medium: Online Resource
    ISSN: 0014-5793 , 1873-3468
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2012
    detail.hit.zdb_id: 212746-5
    detail.hit.zdb_id: 1460391-3
    SSG: 12
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  • 6
    In: Biomolecules, MDPI AG, Vol. 11, No. 8 ( 2021-08-12), p. 1196-
    Abstract: BceF is a bacterial tyrosine kinase (BY-kinase) from Burkholderia cepacia, a Gram-negative bacterium accountable for respiratory infections in immunocompromised and cystic fibrosis patients. BceF is involved in the production of exopolysaccharides secreted to the biofilm matrix and promotes resistant and aggressive infections. BY-kinases share no homology with mammalian kinases, and thereby offer a means to develop novel and specific antivirulence drugs. Here, we report the crystal structure of the BceF kinase domain at 1.85 Å resolution. The isolated BceF kinase domain is assembled as a dimer in solution and crystallized as a dimer in the asymmetric unit with endogenous adenosine-diphosphate bound at the active sites. The low enzymatic efficiency measured in solution may be explained by the partial obstruction of the active sites at the crystallographic dimer interface. This study provides insights into self-assembly and the specific activity of isolated catalytic domains. Several unique variations around the active site compared to other BY-kinases may allow for structure-based design of specific inhibitors to target Burkholderia cepacia virulence.
    Type of Medium: Online Resource
    ISSN: 2218-273X
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2701262-1
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  • 7
    In: iScience, Elsevier BV, Vol. 25, No. 1 ( 2022-01), p. 103717-
    Type of Medium: Online Resource
    ISSN: 2589-0042
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
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  • 8
    Online Resource
    Online Resource
    International Union of Crystallography (IUCr) ; 2015
    In:  Acta Crystallographica Section D Biological Crystallography Vol. 71, No. 12 ( 2015-12-01), p. 2433-2448
    In: Acta Crystallographica Section D Biological Crystallography, International Union of Crystallography (IUCr), Vol. 71, No. 12 ( 2015-12-01), p. 2433-2448
    Abstract: Geobacillus stearothermophilus T-6 is a Gram-positive thermophilic soil bacterium that contains a battery of degrading enzymes for the utilization of plant cell-wall polysaccharides, including xylan, arabinan and galactan. A 9.4 kb gene cluster has recently been characterized in G. stearothermophilus that encodes a number of galactan-utilization elements. A key enzyme of this degradation system is Gan42B, an intracellular GH42 β-galactosidase capable of hydrolyzing short β-1,4-galactosaccharides into galactose units, making it of high potential for various biotechnological applications. The Gan42B monomer is made up of 686 amino acids, and based on sequence homology it was suggested that Glu323 is the catalytic nucleophile and Glu159 is the catalytic acid/base. In the current study, the detailed three-dimensional structure of wild-type Gan42B (at 2.45 Å resolution) and its catalytic mutant E323A (at 2.50 Å resolution), as determined by X-ray crystallography, are reported. These structures demonstrate that the three-dimensional structure of the Gan42B monomer generally correlates with the overall fold observed for GH42 proteins, consisting of three main domains: an N-terminal TIM-barrel domain, a smaller mixed α/β domain, and the smallest all-β domain at the C-terminus. The two catalytic residues are located in the TIM-barrel domain in a pocket-like active site such that their carboxylic functional groups are about 5.3 Å from each other, consistent with a retaining mechanism. The crystal structure demonstrates that Gan42B is a homotrimer, resembling a flowerpot in general shape, in which each monomer interacts with the other two to form a cone-shaped tunnel cavity in the centre. The cavity is ∼35 Å at the wide opening and ∼5 Å at the small opening and ∼40 Å in length. The active sites are situated at the interfaces between the monomers, so that every two neighbouring monomers participate in the formation of each of the three active sites of the trimer. They are located near the small opening of the cone tunnel, all facing the centre of the cavity. The biological relevance of this trimeric structure is supported by independent results obtained from gel-permeation chromatography. These data and their comparison to the structural data of related GH42 enzymes are used for a more general discussion concerning structure–activity aspects in this GH family.
    Type of Medium: Online Resource
    ISSN: 1399-0047
    Language: Unknown
    Publisher: International Union of Crystallography (IUCr)
    Publication Date: 2015
    detail.hit.zdb_id: 2020492-9
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  • 9
    Online Resource
    Online Resource
    Elsevier BV ; 2020
    In:  Structure Vol. 28, No. 3 ( 2020-03), p. 301-313.e6
    In: Structure, Elsevier BV, Vol. 28, No. 3 ( 2020-03), p. 301-313.e6
    Type of Medium: Online Resource
    ISSN: 0969-2126
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 1213087-4
    SSG: 12
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  • 10
    In: Biochemical Journal, Portland Press Ltd., Vol. 422, No. 1 ( 2009-08-15), p. 73-82
    Abstract: Arabinanases are glycosidases that hydrolyse α-(1→5)- arabinofuranosidic linkages found in the backbone of the pectic polysaccharide arabinan. Here we describe the biochemical characterization and the enzyme–substrate crystal structure of an inverting family 43 arabinanase from Geobacillus stearothermophilus T-6 (AbnB). Based on viscosity and reducing power measurements, and based on product analysis for the hydrolysis of linear arabinan by AbnB, the enzyme works in an endo mode of action. Isothermal titration calorimetry studies of a catalytic mutant with various arabino-oligosaccharides suggested that the enzyme active site can accommodate at least five arabinose units. The crystal structure of AbnB was determined at 1.06 Å (1 Å=0.1 nm) resolution, revealing a single five-bladed-β-propeller fold domain. Co-crystallization of catalytic mutants of the enzyme with different substrates allowed us to obtain complex structures of AbnBE201A with arabinotriose and AbnBD147A with arabinobiose. Based on the crystal structures of AbnB together with its substrates, the position of the three catalytic carboxylates: Asp27, the general base; Glu201, the general acid; and Asp147, the pKa modulator, is in agreement with their putative catalytic roles. In the complex structure of AbnBE201A with arabinotriose, a single water molecule is located 2.8 Å from Asp27 and 3.7 Å from the anomeric carbon. The position of this water molecule is kept via hydrogen bonding with a conserved tyrosine (Tyr229) that is 2.6 Å distant from it. The location of this molecule suggests that it can function as the catalytic water molecule in the hydrolysis reaction, resulting in the inversion of the anomeric configuration of the product.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    RVK:
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2009
    detail.hit.zdb_id: 1473095-9
    detail.hit.zdb_id: 2969-5
    SSG: 12
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