Schneider G

References (7)

Title : The AEROPATH project targeting Pseudomonas aeruginosa: crystallographic studies for assessment of potential targets in early-stage drug discovery. - Moynie_2013_Acta.Crystallogr.Sect.F.Struct.Biol.Cryst.Commun_69_25
Author(s) : Moynie L , Schnell R , McMahon SA , Sandalova T , Boulkerou WA , Schmidberger JW , Alphey M , Cukier C , Duthie F , Kopec J , Liu H , Jacewicz A , Hunter WN , Naismith JH , Schneider G
Ref : Acta Crystallographica Sect F Struct Biol Cryst Commun , 69 :25 , 2013
Abstract : Bacterial infections are increasingly difficult to treat owing to the spread of antibiotic resistance. A major concern is Gram-negative bacteria, for which the discovery of new antimicrobial drugs has been particularly scarce. In an effort to accelerate early steps in drug discovery, the EU-funded AEROPATH project aims to identify novel targets in the opportunistic pathogen Pseudomonas aeruginosa by applying a multidisciplinary approach encompassing target validation, structural characterization, assay development and hit identification from small-molecule libraries. Here, the strategies used for target selection are described and progress in protein production and structure analysis is reported. Of the 102 selected targets, 84 could be produced in soluble form and the de novo structures of 39 proteins have been determined. The crystal structures of eight of these targets, ranging from hypothetical unknown proteins to metabolic enzymes from different functional classes (PA1645, PA1648, PA2169, PA3770, PA4098, PA4485, PA4992 and PA5259), are reported here. The structural information is expected to provide a firm basis for the improvement of hit compounds identified from fragment-based and high-throughput screening campaigns.
ESTHER : Moynie_2013_Acta.Crystallogr.Sect.F.Struct.Biol.Cryst.Commun_69_25
PubMedSearch : Moynie_2013_Acta.Crystallogr.Sect.F.Struct.Biol.Cryst.Commun_69_25
PubMedID: 23295481
Gene_locus related to this paper: pseae-PA2086

Title : Context-based identification of protein-protein interfaces and hot-spot residues - Geppert_2011_Chem.Biol_18_344
Author(s) : Geppert T , Hoy B , Wessler S , Schneider G
Ref : Chemical Biology , 18 :344 , 2011
Abstract : Reliable determination of protein-protein interaction sites is of critical importance for structure-based design of small molecules modulating protein function through macromolecular interfaces. We present an alignment-free computational method for prediction of protein-protein interface residues. The method ("iPred") is based on a knowledge-based scoring function adapted from the field of protein folding and small molecule docking. Based on a training set of 394 hetero-dimeric proteins iPred achieves sustained accuracy on an external unbound test set. Prediction robustness was assessed from more than 1500 diverse complexes containing homo- and hetero-dimers. The technique does not rely on sequence conservation, so that rapid interface identification is possible even for proteins for which homologs are unknown or lack conserved residue patterns in interface region. Functional "hot-spot" residues are enriched among the predicted interface residues, rendering the method predestined for macromolecular binding site identification and drug design studies aiming at modulating protein-protein interaction that might influence protein function. For a comparative structural model of peptidase HtrA from Helicobacter pylori, we performed mutation studies for predicted hot-spot residues, which were confirmed as functionally relevant for HtrA activity or oligomerization.
ESTHER : Geppert_2011_Chem.Biol_18_344
PubMedSearch : Geppert_2011_Chem.Biol_18_344
PubMedID: 21439479

Title : Structure of HI-6*sarin-acetylcholinesterase determined by X-ray crystallography and molecular dynamics simulation: reactivator mechanism and design - Ekstrom_2009_PLoS.One_4_e5957
Author(s) : Ekstrom F , Hornberg A , Artursson E , Hammarstrom LG , Schneider G , Pang YP
Ref : PLoS ONE , 4 :e5957 , 2009
Abstract : Organophosphonates such as isopropyl metylphosphonofluoridate (sarin) are extremely toxic as they phosphonylate the catalytic serine residue of acetylcholinesterase (AChE), an enzyme essential to humans and other species. Design of effective AChE reactivators as antidotes to various organophosphonates requires information on how the reactivators interact with the phosphonylated AChEs. However, such information has not been available hitherto because of three main challenges. First, reactivators are generally flexible in order to change from the ground state to the transition state for reactivation; this flexibility discourages determination of crystal structures of AChE in complex with effective reactivators that are intrinsically disordered. Second, reactivation occurs upon binding of a reactivator to the phosphonylated AChE. Third, the phosphorous conjugate can develop resistance to reactivation. We have identified crystallographic conditions that led to the determination of a crystal structure of the sarin(nonaged)-conjugated mouse AChE in complex with [(E)-[1-[(4-carbamoylpyridin-1-ium-1-yl)methoxymethyl]pyridin-2-ylidene]methyl]-o xoazanium dichloride (HI-6) at a resolution of 2.2 A. In this structure, the carboxyamino-pyridinium ring of HI-6 is sandwiched by Tyr124 and Trp286, however, the oxime-pyridinium ring is disordered. By combining crystallography with microsecond molecular dynamics simulation, we determined the oxime-pyridinium ring structure, which shows that the oxime group of HI-6 can form a hydrogen-bond network to the sarin isopropyl ether oxygen, and a water molecule is able to form a hydrogen bond to the catalytic histidine residue and subsequently deprotonates the oxime for reactivation. These results offer insights into the reactivation mechanism of HI-6 and design of better reactivators.
ESTHER : Ekstrom_2009_PLoS.One_4_e5957
PubMedSearch : Ekstrom_2009_PLoS.One_4_e5957
PubMedID: 19536291
Gene_locus related to this paper: mouse-ACHE

Title : Application of a sensitive collection heuristic for very large protein families: evolutionary relationship between adipose triglyceride lipase (ATGL) and classic mammalian lipases - Schneider_2006_BMC.Bioinformatics_7_164
Author(s) : Schneider G , Neuberger G , Wildpaner M , Tian S , Berezovsky I , Eisenhaber F
Ref : BMC Bioinformatics , 7 :164 , 2006
Abstract : BACKGROUND: Manually finding subtle yet statistically significant links to distantly related homologues becomes practically impossible for very populated protein families due to the sheer number of similarity searches to be invoked and analyzed. The unclear evolutionary relationship between classical mammalian lipases and the recently discovered human adipose triglyceride lipase (ATGL; a patatin family member) is an exemplary case for such a problem.
RESULTS: We describe an unsupervised, sensitive sequence segment collection heuristic suitable for assembling very large protein families. It is based on fan-like expanding, iterative database searches. To prevent inclusion of unrelated hits, additional criteria are introduced: minimal alignment length and overlap with starting sequence segments, finding starting sequences in reciprocal searches, automated filtering for compositional bias and repetitive patterns. This heuristic was implemented as FAMILYSEARCHER in the ANNIE sequence analysis environment and applied to search for protein links between the classical lipase family and the patatin-like group. CONCLUSION: The FAMILYSEARCHER is an efficient tool for tracing distant evolutionary relationships involving large protein families. Although classical lipases and ATGL have no obvious sequence similarity and differ with regard to fold and catalytic mechanism, homology links detected with FAMILYSEARCHER show that they are evolutionarily related. The conserved sequence parts can be narrowed down to an ancestral core module consisting of three beta-strands, one alpha-helix and a turn containing the typical nucleophilic serine. Moreover, this ancestral module also appears in numerous enzymes with various substrate specificities, but that critically rely on nucleophilic attack mechanisms.
ESTHER : Schneider_2006_BMC.Bioinformatics_7_164
PubMedSearch : Schneider_2006_BMC.Bioinformatics_7_164
PubMedID: 16551354

Title : The pathogenicity island-associated K15 capsule determinant exhibits a novel genetic structure and correlates with virulence in uropathogenic Escherichia coli strain 536 - Schneider_2004_Infect.Immun_72_5993
Author(s) : Schneider G , Dobrindt U , Bruggemann H , Nagy G , Janke B , Blum-Oehler G , Buchrieser C , Gottschalk G , Emody L , Hacker J
Ref : Infect Immun , 72 :5993 , 2004
Abstract : The K15 capsule determinant of uropathogenic Escherichia coli strain 536 (O6:K15:H31) is part of a novel 79.6-kb pathogenicity island (PAI) designated PAI V536 that is absent from the genome of nonpathogenic E. coli K-12 strain MG1655. PAI V536 shows typical characteristics of a composite PAI that is associated with the pheV tRNA gene and contains the pix fimbriae determinant as well as genes coding for a putative phosphoglycerate transport system, an autotransporter protein, and hypothetical open reading frames. A gene cluster coding for a putative general secretion pathway system, together with a kps(K15) determinant, is localized downstream of a truncated pheV gene ('pheV) also present in this chromosomal region. The distribution of genes present on PAI V536 was studied by PCR in different pathogenic and nonpathogenic E. coli isolates of various sources. Analysis of the 20-kb kps locus revealed a so far unknown genetic organization. Generally, the kps(K15) gene cluster resembles that of group 2 and 3 capsules, where two conserved regions (regions 1 and 3) are located up- or downstream of a highly variable serotype-specific region (region 2). Interestingly, recombination of a group 2 and 3 determinant may have been involved in the evolution of the K15 capsule-encoding gene cluster. Expression of the K15 capsule is important for virulence in a murine model of ascending urinary tract infection but not for serum resistance of E. coli strain 536.
ESTHER : Schneider_2004_Infect.Immun_72_5993
PubMedSearch : Schneider_2004_Infect.Immun_72_5993
PubMedID: 15385503
Gene_locus related to this paper: ecolx-q707d7

Title : Crystal structure of aclacinomycin methylesterase with bound product analogues: implications for anthracycline recognition and mechanism - Jansson_2003_J.Biol.Chem_278_39006
Author(s) : Jansson A , Niemi J , Mantsala P , Schneider G
Ref : Journal of Biological Chemistry , 278 :39006 , 2003
Abstract : Aclacinomycin methylesterase (RdmC) is one of the tailoring enzymes that modify the aklavinone skeleton in the biosynthesis of anthracyclines in Streptomyces species. The crystal structures of this enzyme from Streptomyces purpurascens in complex with the product analogues 10-decarboxymethylaclacinomycin T and 10-decarboxymethylaclacinomycin A were determined to nominal resolutions of 1.45 and 1.95 A, respectively. RdmC is built up of two domains. The larger alpha/beta domain shows the common alpha/beta hydrolase fold, whereas the smaller domain is alpha-helical. The active site and substrate binding pocket are located at the interface between the two domains. Decarboxymethylaclacinomycin T and decarboxymethylaclacinomycin A bind close to the catalytic triad (Ser102-His276-Asp248) in a hydrophobic pocket, with the sugar moieties located at the surface of the enzyme. The binding of the ligands is dominated by hydrophobic interactions, and specificity appears to be controlled mainly by the shape of the binding pocket rather than through specific hydrogen bonds. Mechanistic key features consistent with the structure of complexes of RdmC with product analogues are Ser102 acting as nucleophile and transition state stabilization by an oxyanion hole formed by the backbone amides of residues Gly32 and Met103.
ESTHER : Jansson_2003_J.Biol.Chem_278_39006
PubMedSearch : Jansson_2003_J.Biol.Chem_278_39006
PubMedID: 12878604
Gene_locus related to this paper: ecoli-rdmC , strpu-rdmC

Title : Genetic structure and distribution of four pathogenicity islands (PAI I(536) to PAI IV(536)) of uropathogenic Escherichia coli strain 536 - Dobrindt_2002_Infect.Immun_70_6365
Author(s) : Dobrindt U , Blum-Oehler G , Nagy G , Schneider G , Johann A , Gottschalk G , Hacker J
Ref : Infect Immun , 70 :6365 , 2002
Abstract : For the uropathogenic Escherichia coli strain 536 (O6:K15:H31), the DNA sequences of three pathogenicity islands (PAIs) (PAI I(536) to PAI III(536)) and their flanking regions (about 270 kb) were determined to further characterize the virulence potential of this strain. PAI I(536) to PAI III(536) exhibit features typical of PAIs, such as (i) association with tRNA-encoding genes; (ii) G+C content differing from that of the host genome; (iii) flanking repeat structures; (iv) a mosaic-like structure comprising a multitude of functional, truncated, and nonfunctional putative open reading frames (ORFs) with known or unknown functions; and (v) the presence of many fragments of mobile genetic elements. PAI I(536) to PAI III(536) range between 68 and 102 kb in size. Although these islands contain several ORFs and known virulence determinants described for PAIs of other extraintestinal pathogenic E. coli (ExPEC) isolates, they also consist of as-yet-unidentified ORFs encoding putative virulence factors. The genetic structure of PAI IV(536), which represents the core element of the so-called high-pathogenicity island encoding a siderophore system initially identified in pathogenic yersiniae, was further characterized by sample sequencing. For the first time, multiple PAI sequences (PAI I(536) to PAI IV(536)) in uropathogenic E. coli were studied and their presence in several wild-type E. coli isolates was extensively investigated. The results obtained suggest that these PAIs or at least large fragments thereof are detectable in other pathogenic E. coli isolates. These results support our view that the acquisition of large DNA regions, such as PAIs, by horizontal gene transfer is an important factor for the evolution of bacterial pathogens.
ESTHER : Dobrindt_2002_Infect.Immun_70_6365
PubMedSearch : Dobrindt_2002_Infect.Immun_70_6365
PubMedID: 12379716
Gene_locus related to this paper: ecoli-IROD