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The tyrosine gate as a potential entropic lever in the receptor-binding site of the bacterial adhesin FimH 总被引:1,自引:0,他引:1
Wellens A Lahmann M Touaibia M Vaucher J Oscarson S Roy R Remaut H Bouckaert J 《Biochemistry》2012,51(24):4790-4799
Uropathogenic Escherichia coli (UPEC) are the major causative agents of urinary tract infections. During infection, UPEC adhere to mannosylated glycoreceptors on the urothelium via the FimH adhesin located at the tip of type 1 pili. Synthetic FimH antiadhesives such as alkyl and phenyl α-D-mannopyranosides are thus ideal candidates for the chemical interception of this crucial step in pathogenesis. The crystal structures of the FimH lectin domain in its ligand-free form and in complexes with eight medium- and high-affinity mannopyranoside inhibitors are presented. The thermodynamic profiles of the FimH-inhibitor interactions indicate that the binding of FimH to α-D-mannopyranose is enthalpy-driven and has a negative entropic change. Addition of a hydrophobic aglycon influences the binding enthalpy and can induce a favorable entropic change. The alleviation of the entropic cost is at least in part explained by increased dynamics in the tyrosine gate (Tyr48 and Tyr137) of the FimH receptor-binding site upon binding of the ligand. Ligands with a phenyl group directly linked to the anomeric oxygen of α-D-mannose introduce the largest dynamics into the Tyr48 side chain, because conjugation with the anomeric oxygen of α-D-mannose forces the aromatic aglycon into a conformation that comes into close contact (≈2.65 ?) with Tyr48. A propargyl group in this position predetermines the orientation of the aglycon and significantly decreases affinity. FimH has the highest affinity for α-D-mannopyranosides substituted with hydrophobic aglycons that are compatible in shape and electrostatic properties to the tyrosine gate, such as heptyl α-D-mannose. 相似文献
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Anneleen Decock Maté Ongenaert Jasmien Hoebeeck Katleen De Preter Gert Van Peer Wim Van Criekinge Ruth Ladenstein Johannes H Schulte Rosa Noguera Raymond L Stallings An Van Damme Geneviève Laureys Jo?lle Vermeulen Tom Van Maerken Frank Speleman Jo Vandesompele 《Genome biology》2012,13(10):R95
Background
Accurate outcome prediction in neuroblastoma, which is necessary to enable the optimal choice of risk-related therapy, remains a challenge. To improve neuroblastoma patient stratification, this study aimed to identify prognostic tumor DNA methylation biomarkers.Results
To identify genes silenced by promoter methylation, we first applied two independent genome-wide methylation screening methodologies to eight neuroblastoma cell lines. Specifically, we used re-expression profiling upon 5-aza-2''-deoxycytidine (DAC) treatment and massively parallel sequencing after capturing with a methyl-CpG-binding domain (MBD-seq). Putative methylation markers were selected from DAC-upregulated genes through a literature search and an upfront methylation-specific PCR on 20 primary neuroblastoma tumors, as well as through MBD- seq in combination with publicly available neuroblastoma tumor gene expression data. This yielded 43 candidate biomarkers that were subsequently tested by high-throughput methylation-specific PCR on an independent cohort of 89 primary neuroblastoma tumors that had been selected for risk classification and survival. Based on this analysis, methylation of KRT19, FAS, PRPH, CNR1, QPCT, HIST1H3C, ACSS3 and GRB10 was found to be associated with at least one of the classical risk factors, namely age, stage or MYCN status. Importantly, HIST1H3C and GNAS methylation was associated with overall and/or event-free survival.Conclusions
This study combines two genome-wide methylation discovery methodologies and is the most extensive validation study in neuroblastoma performed thus far. We identified several novel prognostic DNA methylation markers and provide a basis for the development of a DNA methylation-based prognostic classifier in neuroblastoma. 相似文献3.
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M. H. van den Berg Arthur A. M Wilde E. O. Robles de Medina Henk Meyer J. L. M. C. Geelen Roselie J. E. Jongbloed Hein J. J. Wellens Joep P. M. Geraedts 《Human genetics》1997,100(3-4):356-361
The Romano Ward long QT syndrome (LQTS) has an autosomal dominant mode of inheritance. Patients suffer from syncopal attacks
often resulting in sudden cardiac death. The main diagnostic parameter is a prolonged QT(c) interval as judged by electro-cardiographic investigation. LQTS is a genetically heterogeneous disease with four loci having
been identified to date: chromosome 11p15.5 (LQT1), 7q35–36 (LQT2), 3p21–24 (LQT3) and 4q25–26 (LQT4). The corresponding genes
code for potassium channels KVLQT1 (LQT1)and HERG (LQT2) and the sodium channel SCN5A (LQT3). The KVLQT1 gene is characterized
by six transmembrane domains (S1– S6), a pore region situated between the S5 and S6 domains and a C-terminal domain accounting
for approximately 60% of the channel. This domain is thought to be co-associated with another protein, viz. minK (minimal
potassium channel). We have studied a Romano Ward family with several affected individuals showing a severe LQTS phenotype
(syncopes and occurrence of sudden death). Most affected individuals had considerable prolongations of QT(c). By using haplotyping with a set of markers covering the four LQT loci, strong linkage was established to the LQT1 locus,
whereas the other loci (LQT2, LQT3 and LQT4) could be excluded. Single-strand conformation polymorphism analysis and direct
sequencing were used to screen the KVLQT1 gene for mutations in the S1–S6 region, including the pore domain. We identified
a Gly-216-Arg substitution in the S6 transmembrane domain of KVLQT1. The mutation was present in all affected family members
but absent in normal control individuals, providing evidence that the mutated KVLQT1-gene product indeed caused LQTS in this
family. The mutated KVLQT1-gene product thus probably results in a dominant negative suppression of channel activity.
Received: 25 March 1997 / Accepted: 21 April 1997 相似文献
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Jasmien Taildeman Claudina A. Pérez-Novo Isabelle Rottiers Liesbeth Ferdinande Anouk Waeytens Veerle De Colvenaer Claus Bachert Pieter Demetter Wim Waelput Katleen Braet Claude A. Cuvelier 《Histochemistry and cell biology》2009,131(6):703-711
Mast cells are immune cells that produce and secrete a variety of mediators and cytokines that influence various inflammatory
and immune processes. Leptin is a cytokine regulating metabolic, endocrine as well as immune functions via the leptin receptor
which is expressed by many immune cells. However, there are no data about leptin receptor expression in mast cells. Immunohistochemical
and immunofluorescent double stainings showed the expression of leptin and leptin receptors in mast cells in human skin and
several parts of the respiratory, gastrointestinal and urogenital tract. Leptin was expressed in mast cells expressing the
classification marker chymase, whereas a variable expression was observed in tryptase positive mast cells. For leptin receptors,
the expression pattern was tissue dependent and not related to tryptase or chymase expression. Our results demonstrate the
expression of leptin and leptin receptors on mast cells, suggesting paracrine and/or autocrine immunomodulatory effects of
leptin on mast cells. 相似文献
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Filip Pattyn Jasmien Hoebeeck Piet Robbrecht Evi Michels Anne De Paepe Guy Bottu David Coornaert Robert Herzog Frank Speleman Jo Vandesompele 《BMC bioinformatics》2006,7(1):496