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PubMed2005

NMR snapshots of a fluctuating protein structure: ubiquitin at 30 bar-3 kbar.

Conformational fluctuation plays a key role in protein function, but we know little about the associated structural changes. Here we present a general method for elucidating, at the atomic level, a large-scale shape change of a protein molecule in solution undergoing conformational fluctuation. The method utilizes the intimate relationship between conformation and partial molar volume and determines three-dimensional structures of a protein at different pressures using variable pressure NMR technique, whereby NOE distance and torsion angle constraints are used to create average coordinates. Ubiquitin (pH 4.6 at 20 degrees C) was chosen as the first target, for which structures were determined at 30 bar and at 3 kbar, giving "NMR snapshots" of a fluctuating protein structure at atomic resolution. The result reveals that the helix swings in and out by >3 angstroms with a simultaneous reorientation of the C-terminal segment, providing an "open" conformer suitable for enzyme recognition. Spin relaxation analysis indicates that this fluctuation occurs in the ten microsecond time range with activation volumes -4.2(+/-3.2) and 18.5(+/-3.0) ml/mol for the "closed-to-open" and the "open-to-closed" transitions, respectively.

Humans↗

PubMed2005

Structural snapshots of MTA/AdoHcy nucleosidase along the reaction coordinate provide insights into enzyme and nucleoside flexibility during catalysis.

MTA/AdoHcy nucleosidase (MTAN) irreversibly hydrolyzes the N9-C1' bond in the nucleosides, 5'-methylthioadenosine (MTA) and S-adenosylhomocysteine (AdoHcy) to form adenine and the corresponding thioribose. MTAN plays a vital role in metabolic pathways involving methionine recycling, biological methylation, polyamine biosynthesis, and quorum sensing. Crystal structures of a wild-type (WT) MTAN complexed with glycerol, and mutant-enzyme and mutant-product complexes have been determined at 2.0A, 2.0A, and 2.1A resolution, respectively. The WT MTAN-glycerol structure provides a purine-free model and in combination with the previously solved thioribose-free MTAN-ADE structure, we now have separate apo structures for both MTAN binding subsites. The purine and thioribose-free states reveal an extensive enzyme-immobilized water network in their respective binding subsites. The Asp197Asn MTAN-MTA and Glu12Gln MTAN-MTR.ADE structures are the first enzyme-substrate and enzyme-product complexes reported for MTAN, respectively. These structures provide representative snapshots along the reaction coordinate and allow insight into the conformational changes of the enzyme and the nucleoside substrate. A "catalytic movie" detailing substrate binding, catalysis, and product release is presented.

Amino Acid Substitution↗

PubMed2006

Crystallographic snapshot of a productive glycosylasparaginase-substrate complex.

Glycosylasparaginase (GA) plays an important role in asparagine-linked glycoprotein degradation. A deficiency in the activity of human GA leads to a lysosomal storage disease named aspartylglycosaminuria. GA belongs to a superfamily of N-terminal nucleophile hydrolases that autoproteolytically generate their mature enzymes from inactive single chain protein precursors. The side-chain of the newly exposed N-terminal residue then acts as a nucleophile during substrate hydrolysis. By taking advantage of mutant enzyme of Flavobacterium meningosepticum GA with reduced enzymatic activity, we have obtained a crystallographic snapshot of a productive complex with its substrate (NAcGlc-Asn), at 2.0 A resolution. This complex structure provided us an excellent model for the Michaelis complex to examine the specific contacts critical for substrate binding and catalysis. Substrate binding induces a conformational change near the active site of GA. To initiate catalysis, the side-chain of the N-terminal Thr152 is polarized by the free alpha-amino group on the same residue, mediated by the side-chain hydroxyl group of Thr170. Cleavage of the amide bond is then accomplished by a nucleophilic attack at the carbonyl carbon of the amide linkage in the substrate, leading to the formation of an acyl-enzyme intermediate through a negatively charged tetrahedral transition state.

Amidohydrolases↗

PubMed2004

Snapshot of protein structure evolution reveals conservation of functional dimerization through intertwined folding.

Protein-protein interactions govern a wide range of cellular processes. Molecular recognition responsible for homodimerization and heterodimerization in the rel/NF-kappaB family of eukaryotic transcription factors relies on a small cluster of hydrophobic residues. We have carried out a structural analysis of six NF-kappaB p50 dimer interface mutants; one of them revealed a remarkable alteration. One or possibly both its mutations cause a switch into an intertwined dimer, in which the molecular partners exchange nearly half of their fold. In spite of the extensive swapping of secondary structure elements, the topology within each counterpart is preserved, with a very similar overall structure and minimal changes at the interface. Thus intertwining rescues structure and function from a destabilizing mutation. Since the mutants originate from a directed evolution experiment and are functional, the data provide an evolutionary snapshot of how a protein structure can respond to mutations while maintaining a functional molecular architecture.

Animals↗

PubMed2005

Bladder exstrophy in the newborn: a snapshot of contemporary practice patterns.

OBJECTIVES: To use a large nationwide database to investigate and describe practice patterns in the contemporary management of bladder exstrophy. METHODS: The Healthcare Cost and Utilization Project Nationwide Inpatient Sample (1988 to 2000) was queried to identify infants with bladder exstrophy hospitalized during the first week after birth. Admission and disposition patterns, resource utilization and length of stay, surgical repair trends, and factors associated with in-hospital death were analyzed. RESULTS: We identified 426 hospital admissions of newborns with exstrophy. Most patients (75%) were transferred in from, or out to, other facilities; this was a fundamental feature of early exstrophy care. Racial differences were evident, with Hispanics less likely to be transferred (19% versus 60%, P = 0.001). Among newborns who were not transferred, many (46%) were discharged without bladder surgery. Surgical repair was usually done in a hospital other than the birth hospital; the mean hospital charges for surgery were 75,742 dollars. Of the 5 patients who died after repair, all had undergone surgery at "low-volume" hospitals. The length of stay did not change significantly during the study period, helping to keep resource utilization high in this population. CONCLUSIONS: The results of this study provide a "snapshot" of bladder exstrophy practice patterns during the newborn period between 1988 and 2000. Additional research should investigate whether newborns with exstrophy are receiving optimal care, including appropriate timing of surgery, equitable transfers to tertiary centers, and reconstruction at centers with adequate volume and experience.

Bladder Exstrophy↗

PubMed1996

Can a "snapshot" sagittal view of the cervix by transvaginal ultrasonography predict active preterm labor?

OBJECTIVE: Our purpose was to test the hypothesis that wedging of the cervical internal os determined by transvaginal ultrasonography is associated with premature labor and delivery. STUDY DESIGN: Seventy patients admitted to the hospital for threatened preterm labor were evaluated by transvaginal ultrasonography before institution of therapy. Bivariate and logistic regression analyses were performed to determine the variables that made a significant contribution to the prediction of preterm delivery. RESULTS: Preterm delivery was significantly associated with the presence of cervical wedging, as noted on cervical scan, and with short cervical length. A history of previous preterm delivery was of marginal significance as a predictor of preterm delivery (p=0.09). Preterm delivery was not significantly correlated with age, previous voluntary termination of pregnancy, gestational age at the time of study, previous normal spontaneous vaginal delivery, or tocolytic therapy. Use of wedging as a diagnostic test for the prediction of preterm delivery yielded a sensitivity of 100% a specificity of 74.5%, a positive predictive value of 59.4%, and a negative predictive value of 100%. CONCLUSION: The presence of wedging and shorter cervical length was suggestive of true preterm labor requiring aggressive management. A transvaginal ultrasonographic "snapshot" view of the cervix seems to be a more reliable method to evaluate the cervix in patients with threatened premature labor than are uterine contractions alone.

Adult↗

PubMed2002

Typing of multiple single nucleotide polymorphisms in cytokine and receptor genes using SNaPshot.

Associations have been described between polymorphisms in cytokine genes and severity of autoimmune diseases, outcome of infectious disease, and outcome following transplantation. Many methods now exist for typing single nucleotide polymorphisms (SNPs) and these can be applied to typing cytokine gene and cytokine receptor gene variation. A system for typing multiple cytokine and receptor gene polymorphisms using a primer extension method, SNaPshot (Applied Biosystems, Foster City, CA, USA), has been assessed. The development of this methodology may enable other laboratories to type for cytokine SNPs in different populations and facilitate research into the effect of genetic polymorphism in the cytokine network in transplantation and disease.

Adult↗

PubMed2000

Visualization of Taylor-Couette and spiral Poiseuille flows using a snapshot FLASH spatial tagging sequence.

A new magnetic resonance imaging technique was applied to the Taylor-Couette and spiral Poiseuille (Taylor-Couette with superposed mean axial flux) flows for the first time. The experimental technique is a combination of spatial tagging methods and a snapshot FLASH imaging sequence, which allows the full-field visualization of 2-D slices of the flow field, with image acquisition times approximately half a second. By acquiring images every few seconds, direct visualization of flow patterns can be obtained in the form of cinematography. Tagged images of the Taylor-Couette flow were acquired in both the axial and transverse planes and confirmed previously reported numerical predictions of Taylor cell size. Tagged images of the spiral Poiseuille flows verified that the cells in this flow propagate at a higher velocity than the mean axial flow. In addition, intermittent cell formation was observed as the axial flow was increased.

Equipment Design↗

PubMed1993

Snapshots along the reaction coordinate of an SNAr reaction catalyzed by glutathione transferase.

The three-dimensional structures of a class mu glutathione transferase in complex with a transition-state analogue, 1-(S-glutathionyl)-2,4,6-trinitrocyclohexadienate, and a product, 1-(S-glutathionyl)-2,4-dinitrobenzene, of a nucleophilic aromatic substitution (SNAr) reaction have been determined at 1.9- and 2.0-A resolution, respectively. The two structures represent snapshots along the reaction coordinate for the enzyme-catalyzed reaction of glutathione with 1-chloro-2,4-dinitrobenzene and reveal specific interactions between the enzyme, intermediate, and product that are important in catalysis. The geometries of the intermediate and product are used to postulate reaction coordinate motion during catalysis.

Binding Sites↗

PubMed2005

Using MD snapshots in ab initio and DFT calculations: OH vibrations in the first hydration shell around Li+(aq).

The average OH stretching vibrational frequency for the water molecules in the first hydration shell around a Li(+) ion in a dilute aqueous solution was calculated by a hybrid molecular dynamics + quantum-mechanical ("MD + QM") approach. Using geometry configurations from a series of snapshots from an MD simulation, the anharmonic, uncoupled OH stretching frequencies were calculated for 100 first-shell OH oscillators at the B3LYP and HF/6-31G(d,p) levels of theory, explicitly including the first shell and the relevant second shell water molecules into charge-embedded supermolecular QM calculations. Infrared intensity-weighting of the density-of-states (DOS) distributions by means of the squared dipole moment derivatives (which vary by a factor of 20 over the OH stretching frequency band at the B3LYP level), changes the downshift from approximately -205 to -275 cm(-1) at the B3LYP level. Explicit inclusion of relevant third-shell water molecules in the supermolecular cluster leads to a further downshift by approximately -30 cm(-1). Our final estimated average downshift is approximately -305 cm(-1). The experimental value lies somewhere in the range between -290 and -420 cm(-1). Also, the absolute nu(OH) frequency is well reproduced in our calculations. "In-liquid" instantaneous correlation curves between nu(OH) and various typical H-bond strength parameters such as R(O...O), R(H...O), the intramolecular OH bond length, and the IR intensity are presented. Some of these correlations are robust and persist also for the rather distorted instantaneous geometries in the liquid; others are less so.

Journal Article↗

PubMed1994

Absence of snapshot memory of the target view interferes with place navigation learning by rats in the water maze.

Contribution of visual and nonvisual mechanisms to spatial behavior of rats in the Morris water maze was studied with a computerized infrared tracking system, which switched off the room lights when the subject entered the inner circular area of the pool with an escape platform. Naive rats trained under light-dark conditions (L-D) found the escape platform more slowly than rats trained in permanent light (L). After group members were swapped, the L-pretrained rats found under L-D conditions the same target faster and eventually approached latencies attained during L navigation. Performance of L-D-trained rats deteriorated in permanent darkness (D) but improved with continued D training. Thus L-D navigation improves gradually by procedural learning (extrapolation of the start-target azimuth into the zero-visibility zone) but remains impaired by lack of immediate visual feedback rather than by absence of the snapshot memory of the target view.

Animals↗

PubMed2006

Snapshots of tRNA sulphuration via an adenylated intermediate.

Uridine at the first anticodon position (U34) of glutamate, lysine and glutamine transfer RNAs is universally modified by thiouridylase into 2-thiouridine (s2U34), which is crucial for precise translation by restricting codon-anticodon wobble during protein synthesis on the ribosome. However, it remains unclear how the enzyme incorporates reactive sulphur into the correct position of the uridine base. Here we present the crystal structures of the MnmA thiouridylase-tRNA complex in three discrete forms, which provide snapshots of the sequential chemical reactions during RNA sulphuration. On enzyme activation, an alpha-helix overhanging the active site is restructured into an idiosyncratic beta-hairpin-containing loop, which packs the flipped-out U34 deeply into the catalytic pocket and triggers the activation of the catalytic cysteine residues. The adenylated RNA intermediate is trapped. Thus, the active closed-conformation of the complex ensures accurate sulphur incorporation into the activated uridine carbon by forming a catalytic chamber to prevent solvent from accessing the catalytic site. The structures of the complex with glutamate tRNA further reveal how MnmA specifically recognizes its three different tRNA substrates. These findings provide the structural basis for a general mechanism whereby an enzyme incorporates a reactive atom at a precise position in a biological molecule.

Anticodon↗

PubMed2003

X-ray snapshots of the maturation of an antibody response to a protein antigen.

The process whereby the immune system generates antibodies of higher affinities during a response to antigen (affinity maturation) is a prototypical example of molecular evolution. Earlier studies have been confined to antibodies specific for small molecules (haptens) rather than for proteins. We compare the structures of four antibodies bound to the same site on hen egg white lysozyme (HEL) at different stages of affinity maturation. These X-ray snapshots reveal that binding is enhanced, not through the formation of additional hydrogen bonds or van der Waals contacts or by an increase in total buried surface, but by burial of increasing amounts of apolar surface at the expense of polar surface, accompanied by improved shape complementarity. The increase in hydrophobic interactions results from highly correlated rearrangements in antibody residues at the interface periphery, adjacent to the central energetic hot spot. This first visualization of the maturation of antibodies to protein provides insights into the evolution of high affinity in other protein-protein interfaces.

Animals↗

PubMedDate not supplied

Snapshot of HIV pathogenesis in China.

Several reviews have focused on the nature of HIV infection and its spread in various geographical regions of China. In contrast, this review provides a comprehensive update on the prevalence of multiple HIV-1 subtypes, consequent emergence of recombinant and novel forms of HIV-1 in China, and the implications this may have on HIV diversity and the development of effective vaccines. In addition it also examines the dissemination of primary drug resistance in therapy naïve patients, as well as co-infections with two other important viruses-hepatitis B and C. The main purpose of this review is to provide a current snapshot of HIV-1 pathogenesis in China and possibly shed some light on the future of HIV evolution, and potential challenges for future vaccine and anti-retroviral therapeutics against HIV strains in this area.

China↗

PubMedDate not supplied

Snapshot of acute asthma: treatment and outcome of patients with acute asthma treated in Australian emergency departments.

AIMS: To characterize presentations due to acute asthma at Australian emergency departments (ED), including their severity, treatment and disposition. METHODS: This prospective, observational study involved 38 departments of emergency medicine throughout -Australia participating in the Snapshot of Asthma Study Group project 2000 and 2001. Data were collected for patients presenting with acute asthma between 21 August 2000 and 3 September 2000, and 20 August 2001 and 2 September 2001 and included demographics, severity classification, treatment and disposition. RESULTS: There were 1340 acute asthma presentations in the study periods. Of these presentations, 67% were for children aged <15 years. Asthma severity (according to the Australian National Asthma Guidelines classification) was 'mild' in 49% of cases; 'moderate' in 45% of cases; and 'severe' in 6% of cases. Treatment administered included: (i) salbutamol to 90%, (ii) ipratropium bromide to 59% and (iii) corticosteroids to 71%. Only six patients received aminophylline. Spacer use for salbutamol was rare (1%) in adults and only moderate (43%) in children. Sixty-five percent of patients were discharged home from the ED. Less than 1% of patients required ventilatory assistance, of which half was provided non-invasively. One percent of patients were admitted to the intensive-care unit or high-dependency unit. CONCLUSION: Overall adherence to treatment guidelines was good. There appears to be underuse of spacers and corticosteroids in some groups and overuse of ipratropium bromide. The majority of patients are treated and discharged from the ED.

Adolescent↗

PubMed1999

'Stories' or 'snapshots'? A study directed at comparing qualitative and quantitative approaches to curriculum evaluation.

The focus of this paper is a study designed to explore the validity of quantitative approaches of student evaluation in a pre-registration degree programme. As managers of the students' education we were concerned that the quantitative method, which used lecturer criteria, may not fully represent students' views. The approach taken is that of a process-type strategy for curriculum evaluation as described by Parlett and Hamilton (1972). The aim of the study is to produce illuminative data, or students' 'stories' of their educational experiences through use of semi-structured interviews. The results are then compared to the current quantitative measurement tools designed to obtain 'snapshots' of the educational effectiveness of the curriculum. The quantitative measurement tools use Likert scale measurements of teacher-devised criterion statements. The results of the study give a rich source of qualitative data which can be used to inform future curriculum development. However, complete validation of the current quantitative instruments used was not achieved in this study. Student and teacher agendas in respect of important issues pertaining to the course programme were found to differ. Limitations of the study are given. There is discussion of the options open to the management team with regard to future development of curriculum evaluation systems.

Adolescent↗

PubMed1992

[The extension of MR diagnosis in dissecting aortic aneurysms by means of FLASH and snapshot-FLASH sequences].

Using a combination of T1 weighted snapshot-flash sequences and intravenous contrast bolus it was possible to demonstrate intraluminal signal differences in a period of seconds. 5 confirmed aortic lesions were studied; 2 old aortic dissections (with differentiation between the true and false lumen), 1 acute aortic dissection and a partially thrombosed thoracic aortic aneurysm were demonstrated. The advantage of this technique lies in its simplicity and reproducibility. Difficulties in interpreting the intraluminal phases arising from spin echo and flash techniques are made easier by interpreting the available signals from this method.

Aortic Dissection↗

PubMed2004

Crosslinking snapshots of bacterial chemoreceptor squads.

The team signaling model for bacterial chemoreceptors proposes that receptor dimers of different detection specificities form mixed trimers of dimers. These receptor "squads" then recruit the cytoplasmic signaling proteins CheA and CheW to form ternary signaling teams, which typically cluster at the poles of the cell. We devised cysteine-directed in vivo crosslinking approaches to ask whether mixed receptor squads could form in the absence of CheA and CheW and, if so, whether the underlying structural interactions conformed to trimer-of-dimers geometry. One approach used cysteine reporters at positions in the serine (Tsr) and aspartate (Tar) receptors that should form disulfide-linked Tsr approximately Tar products when juxtaposed at the interface of a mixed trimer. Another approach used a cysteine reporter with trigonal geometry near the trimer contact region and a trifunctional maleimide reagent with a spacer length appropriate for capturing the three axial subunits in a trimer of dimers. Both approaches detected mixed receptor-crosslinking products in cells lacking CheA and CheW. Under these conditions, receptor methylation and ligand-binding state had no discernable effect on crosslinking efficiencies. Crosslinking with the trigonal reporter was rapid and did not increase with longer treatment times or higher reagent concentrations, suggesting that this method produces a short-exposure snapshot of the receptor population. The extent of crosslinking indicated that most of the cell's receptor molecules were organized in higher-order groups. Crosslinking in receptor trimer contact mutants correlated with their signaling behaviors, suggesting that trimers of dimers are both structural and functional precursors of chemoreceptor signaling teams in bacteria.

Bacterial Proteins↗