Acta Crystallogr D Struct Biol
February 2024
To identify starting points for therapeutics targeting SARS-CoV-2, the Paul Scherrer Institute and Idorsia decided to collaboratively perform an X-ray crystallographic fragment screen against its main protease. Fragment-based screening was carried out using crystals with a pronounced open conformation of the substrate-binding pocket. Of 631 soaked fragments, a total of 29 hits bound either in the active site (24 hits), a remote binding pocket (three hits) or at crystal-packing interfaces (two hits).
View Article and Find Full Text PDFIntroduction: Grange syndrome (OMIM 602531) is characterized by a constellation of symptoms of hypertension, stenosis, or occlusion of different arteries (including the cerebral, renal, abdominal, and coronary vessels) with a variable occurrence of brachysyndactyly, bone fragility, and congenital heart defects. Learning disabilities were also reported in some cases. Biallelic pathogenic variants in are associated with the syndrome.
View Article and Find Full Text PDFRecent advances in automation have fostered the development of unattended data collection services at a handful of synchrotron facilities worldwide. At the Swiss Light Source, the installation of new high-throughput sample changers at all three macromolecular crystallography beamlines and the commissioning of the Fast Fragment and Compound Screening pipeline created a unique opportunity to automate data acquisition. Here, the DA+ microservice software stack upgrades, implementation of an automatic loop-centering service and deployment of the Smart Digital User (SDU) software for unattended data collection are reported.
View Article and Find Full Text PDFBackground: In this retrospective study, we compared the results from 2 pulmonary valve augmentation techniques in patients undergoing surgical repair of tetralogy of Fallot.
Methods: Between 2015 and 2018, 18 patients had anterior pulmonary valve repair at our institution, and 26 patients had both anterior and posterior pulmonary valve repair.
Results: Patients ranged from 6 months to 30 years of age.
Acta Crystallogr D Struct Biol
August 2022
Continuous developments in cryogenic X-ray crystallography have provided most of our knowledge of 3D protein structures, which has recently been further augmented by revolutionary advances in cryoEM. However, a single structural conformation identified at cryogenic temperatures may introduce a fictitious structure as a result of cryogenic cooling artefacts, limiting the overview of inherent protein physiological dynamics, which play a critical role in the biological functions of proteins. Here, a room-temperature X-ray crystallographic method using temperature as a trigger to record movie-like structural snapshots has been developed.
View Article and Find Full Text PDFActa Crystallogr D Struct Biol
March 2022
Over the last two decades, fragment-based drug discovery (FBDD) has emerged as an effective and efficient method to identify new chemical scaffolds for the development of lead compounds. X-ray crystallography can be used in FBDD as a tool to validate and develop fragments identified as binders by other methods. However, it is also often used with great success as a primary screening technique.
View Article and Find Full Text PDFCardiac fibromas are the second most common benign primary tumour of the heart in the children; the clinical features include chest pain, arrhythmia, low cardiac output due to outflow tract obstruction, and sudden cardiac death. Sports are associated with an increased risk for sudden death in athletes who are affected by cardiovascular conditions predisposing to life-threatening arrhythmias. We present a case report of 10-year-old asymptomatic boy who was referred to the paediatric cardiology department by his general practitioner for cardiac examination before participation in competitive sports.
View Article and Find Full Text PDFThe recognition of oligomannose-type glycans in innate and adaptive immunity is elusive due to multiple closely related isomeric glycan structures. To explore the functions of oligomannoses, we developed a multifaceted approach combining mass spectrometry assignments of oligomannose substructures and the development of a comprehensive oligomannose microarray. This defined microarray encompasses both linear and branched glycans, varying in linkages, branching patterns, and phosphorylation status.
View Article and Find Full Text PDFProtein crystallography (PX) is widely used to drive advanced stages of drug optimization or to discover medicinal chemistry starting points by fragment soaking. However, recent progress in PX could allow for a more integrated role into early drug discovery. Here, we demonstrate for the first time the interplay of high throughput synthesis and high throughput PX.
View Article and Find Full Text PDFFilippi syndrome (MIM #272440), one of the craniodigital syndromes, is a rare genetic entity with autosomal recessive inheritance and characterized by pre- and postnatal growth retardation, microcephaly, distinctive facial appearance, developmental delay/intellectual disability, and variable syndactylies of the fingers and toes. In this report, a further female patient of Filippi syndrome who additionally had a unilateral congenital talipes equinovarus (CTEV), a feature not previously recorded, is described. Genetic testing revealed a novel homozygous frameshift pathogenic variant (c.
View Article and Find Full Text PDFAnomalous origin of coronary artery originating from the pulmonary artery in conjunction with the aorticopulmonary window (APW) is a rare but a significant anomaly in the era of congenital cardiac diseases. The occurrence of anomalous origin of the right coronary artery from the pulmonary artery among the associated anomalies is less than 5%. The severity of the clinical condition of these patients depends on the degree of left-right shunt and compromise of the pulmonary blood flow.
View Article and Find Full Text PDFThe repertoire of glycans expressed by individual cells and tissues is enormous, and various estimates indicate that thousands of different glycans and "glycan determinants" are critical for functional recognition by glycan-binding proteins. Defining the steady-state expression and functional impacts of the human glycome will require a concerted worldwide effort, along with the development of new immunological, genetic, chemical, and biochemical technologies. Here, we describe the generation of smart anti-glycan reagents (SAGRs), recombinant antibodies that recognize novel glycan determinants.
View Article and Find Full Text PDFObjective: A study of the T wave peak-to-end (Tp-e) interval, the Tp-e/QT ratio, and the Tp-e/QTc ratio in pediatric heart transplant recipients (HTRs), a group which has a higher risk of sudden cardiac death than the normal population, has not previously been reported. The aim of this study was to assess alterations in ventricular repolarization using the Tp-e interval, Tp-e/ QT ratio, and Tp-e/QTc ratio in clinically stable pediatric HTRs.
Methods: A total of 13 clinically stable HTRs, 13 patients who had undergone cardiac surgery (CS) under cardiopulmonary bypass, and 16 healthy controls under 18 years of age were retrospectively evaluated.
Objective: The use of fluoroscopy in pediatric catheter ablation has decreased because of mapping systems. In this study, we present the efficiency and reliability of the electroanatomic mapping system in nonfluoroscopic pediatric catheter ablation.
Methods: The medical records of patients aged <18 years who underwent ablation between November 2016 and April 2018 were evaluated.
J Cardiovasc Electrophysiol
August 2018
Background: Optimal management strategy for native aortic coarctation in neonates and young infants is still a matter of debate. The surgical procedure, histopathologic research, and clinical outcome in 15 neonates who underwent surgery after successful balloon angioplasty is the basis of this study.
Method: Between 01 October, 2014 and 01 August, 2017, we enrolled 15 patients with native aortic coarctation for this study.
In general, carbohydrate-lectin interactions are characterized by high specificity but also low affinity. The main reason for the low affinities are desolvation costs, due to the numerous hydroxy groups present on the ligand, together with the typically polar surface of the binding sites. Nonetheless, nature has evolved strategies to overcome this hurdle, most prominently in relation to carbohydrate-lectin interactions of the innate immune system but also in bacterial adhesion, a process key for the bacterium's survival.
View Article and Find Full Text PDFFor many biological processes such as ligand binding, enzymatic catalysis, or protein folding, allosteric regulation of protein conformation and dynamics is fundamentally important. One example is the bacterial adhesin FimH, where the C-terminal pilin domain exerts negative allosteric control over binding of the N-terminal lectin domain to mannosylated ligands on host cells. When the lectin and pilin domains are separated under shear stress, the FimH-ligand interaction switches in a so-called catch-bond mechanism from the low- to high-affinity state.
View Article and Find Full Text PDFKawasaki disease is an acute, systemic vasculitis of unknown etiology. Although gastrointestinal involvement does not belong to the classic diagnostic criteria; diarrhea, abdominal pain, hepatic dysfunction, hydrops of gallbladder, and acute febrile cholestatic jaundice are reported in patients with Kawasaki disease. We describe here two cases presented with fever, and acute jaundice as initial features of Kawasaki disease.
View Article and Find Full Text PDFTarget-directed dynamic combinatorial chemistry (DCC) is an emerging technique for the efficient identification of inhibitors of pharmacologically relevant targets. In this contribution, we present an application for a bacterial target, the lectin FimH, a crucial virulence factor of uropathogenic E. coli being the main cause of urinary tract infections.
View Article and Find Full Text PDFFrequent antibiotic treatment of urinary tract infections has resulted in the emergence of antimicrobial resistance, necessitating alternative treatment options. One such approach centers around FimH antagonists that block the bacterial adhesin FimH, which would otherwise mediate binding of uropathogenic Escherichia coli to the host urothelium to trigger the infection. Although the FimH lectin can adopt three distinct conformations, the evaluation of FimH antagonists has mainly been performed with a truncated construct of FimH locked in one particular conformation.
View Article and Find Full Text PDFFimH is a bacterial lectin found at the tips of type 1 pili of uropathogenic Escherichia coli (UPEC). It mediates shear-enhanced adhesion to mannosylated surfaces. Binding of UPEC to urothelial cells initiates the infection cycle leading to urinary tract infections (UTIs).
View Article and Find Full Text PDFLigand-receptor interactions that are reinforced by mechanical stress, so-called catch-bonds, play a major role in cell-cell adhesion. They critically contribute to widespread urinary tract infections by pathogenic Escherichia coli strains. These pathogens attach to host epithelia via the adhesin FimH, a two-domain protein at the tip of type I pili recognizing terminal mannoses on epithelial glycoproteins.
View Article and Find Full Text PDFUrinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli (UPEC), belong to the most prevalent infectious diseases worldwide. The attachment of UPEC to host cells is mediated by FimH, a mannose-binding adhesin at the tip of bacterial type 1 pili. To date, UTIs are mainly treated with antibiotics, leading to the ubiquitous problem of increasing resistance against most of the currently available antimicrobials.
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