scholarly journals Mechanism of Na+-dependent citrate transport from the structure of an asymmetrical CitS dimer

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
David Wöhlert ◽  
Maria J Grötzinger ◽  
Werner Kühlbrandt ◽  
Özkan Yildiz
Keyword(s):  
Rigid Body ◽  
Drug Targets ◽  
Transport Mechanism ◽  
Transport Mechanisms ◽  
Human Pathogen ◽  
Step Process ◽  
X Ray ◽  
Functional Studies ◽  
The Common ◽  
Important Drug

The common human pathogen Salmonella enterica takes up citrate as a nutrient via the sodium symporter SeCitS. Uniquely, our 2.5 Å x-ray structure of the SeCitS dimer shows three different conformations of the active protomer. One protomer is in the outside-facing state. Two are in different inside-facing states. All three states resolve the substrates in their respective binding environments. Together with comprehensive functional studies on reconstituted proteoliposomes, the structures explain the transport mechanism in detail. Our results indicate a six-step process, with a rigid-body 31° rotation of a helix bundle that translocates the bound substrates by 16 Å across the membrane. Similar transport mechanisms may apply to a wide variety of related and unrelated secondary transporters, including important drug targets.

Ionic homeostasis and subcellular element compartmentation

1990 ◽  
Vol 48 (2) ◽  
pp. 150-151
Author(s):  
Ann LeFurgey ◽  
Peter Ingram ◽  
J.J. Blum ◽  
M.C. Carney ◽  
L.A. Hawkey ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Ionic Homeostasis ◽  
X Ray ◽  
Functional Studies ◽  
Cell Compartments ◽  
X Ray Imaging ◽  
Resolution Electron ◽  
Multiple Cell ◽  
Role Of Zn

Subcellular compartments commonly identified and analyzed by high resolution electron probe x-ray microanalysis (EPXMA) include mitochondria, cytoplasm and endoplasmic or sarcoplasmic reticulum. These organelles and cell regions are of primary importance in regulation of cell ionic homeostasis. Correlative structural-functional studies, based on the static probe method of EPXMA combined with biochemical and electrophysiological techniques, have focused on the role of these organelles, for example, in maintaining cell calcium homeostasis or in control of excitation-contraction coupling. New methods of real time quantitative x-ray imaging permit simultaneous examination of multiple cell compartments, especially those areas for which both membrane transport properties and element content are less well defined, e.g. nuclei including euchromatin and heterochromatin, lysosomes, mucous granules, storage vacuoles, microvilli. Investigations currently in progress have examined the role of Zn-containing polyphosphate vacuoles in the metabolism of Leishmania major, the distribution of Na, K, S and other elements during anoxia in kidney cell nuclel and lysosomes; the content and distribution of S and Ca in mucous granules of cystic fibrosis (CF) nasal epithelia; the uptake of cationic probes by mltochondria in cultured heart ceils; and the junctional sarcoplasmic retlculum (JSR) in frog skeletal muscle.

Discovery of an Unexpected Similarity in Ligand Binding Between BRD4 and PPARγ

2019 ◽  
Author(s):  
Lina Humbeck ◽  
Jette Pretzel ◽  
Saskia Spitzer ◽  
Oliver Koch
Keyword(s):  
Cancer Therapy ◽  
Drug Targets ◽  
Synergistic Effects ◽  
Complex Structure ◽  
Peroxisome Proliferator ◽  
Resistance Development ◽  
Peroxisome Proliferator Activated Receptor ◽  
Starting Point ◽  
Fundamental Research ◽  
Important Drug

Knowledge about interrelationships between different proteins is crucial in fundamental research for the elucidation of protein networks and pathways. Furthermore, it is especially critical in chemical biology to identify further key regulators of a disease and to take advantage of polypharmacology effects. A comprehensive scaffold-based analysis uncovered an unexpected relationship between bromodomain-containing protein 4 (BRD4) and peroxisome-proliferator activated receptor gamma (PPARγ). They are both important drug targets for cancer therapy and many more important diseases. Both proteins share binding site similarities near a common hydrophobic subpocket which should allow the design of a polypharmacology-based ligand targeting both proteins. Such a dual-BRD4-PPARγ-modulator could show synergistic effects with a higher efficacy or delayed resistance development in, for example, cancer therapy. Thereon, a complex structure of sulfasalazine was obtained that involves two bromodomains and could be a potential starting point for the design of a bivalent BRD4 inhibitor.

scholarly journals 3D Ore Characterization as a Paradigm Shift for Process Design and Simulation in Mineral Processing

2021 ◽  
Author(s):  
Pratama Istiadi Guntoro ◽  
Yousef Ghorbani ◽  
Jan Rosenkranz
Keyword(s):  
Process Design ◽  
Paradigm Shift ◽  
Mineral Processing ◽  
Analysis Tool ◽  
Micro Computed Tomography ◽  
X Ray ◽  
Automated Mineralogy ◽  
Process Mineralogy ◽  
The Common ◽  
Ore Characterization

AbstractCurrent advances and developments in automated mineralogy have made it a crucial key technology in the field of process mineralogy, allowing better understanding and connection between mineralogy and the beneficiation process. The latest developments in X‑ray micro-computed tomography (µCT) have shown a great potential to let it become the next-generation automated mineralogy technique. µCT’s main benefit lies in its capability to allow 3D monitoring of the internal structure of the ore sample at resolutions down to a few hundred nanometers, thus excluding the common stereological error in conventional 2D analysis. Driven by the technological and computational progress, µCT is constantly developing as an analysis tool and successively it will become an essential technique in the field of process mineralogy. This study aims to assess the potential application of µCT systems, for 3D ore characterization through relevant case studies. The opportunities and platforms that µCT 3D ore characterization provides for process design and simulation in mineral processing are presented.

Techniques to examine nucleotide binding by pseudokinases

2013 ◽  
Vol 41 (4) ◽  
pp. 975-980 ◽  
Author(s):  
Isabelle S. Lucet ◽  
Jeffrey J. Babon ◽  
James M. Murphy
Keyword(s):  
Signal Transduction ◽  
Drug Targets ◽  
Nucleotide Binding ◽  
Biological Functions ◽  
Binding Properties ◽  
Catalytic Activities ◽  
Functional Studies ◽  
Signalling Molecules ◽  
Advantages And Disadvantages ◽  
Human Kinome

Approximately 10% of the human kinome has been classified as pseudokinases due to the absence of one or more of three motifs known to play key roles in the catalytic activities of protein kinases. Structural and functional studies are now emerging, reclassifying this ‘dead’ kinase family as essential signalling molecules that act as crucial modulators of signal transduction. This raises the prospect that pseudokinases may well represent an as-yet-unexplored class of drug targets. However, the extent to which nucleotide binding and catalytic activity contribute to the biological functions of pseudokinases remains an area of great controversy. In the present review, we discuss the advantages and disadvantages of the different methods employed to characterize the nucleotide-binding properties and activity of pseudokinases.

scholarly journals On the X-ray Diagnosis of Gallstones in the Common Duct

2015 ◽  
Vol 57 (1) ◽  
pp. e5-e8
Author(s):  
M. Simon ◽  
M. D. Stockholm
Keyword(s):  
Common Duct ◽  
X Ray ◽  
The Common

Relative Reactivity Trends OP High Temperature Superconductor Phases

1992 ◽  
Vol 275 ◽  
Author(s):  
David R. Riley ◽  
Ji-Ping Zhou ◽  
A. Manthiram ◽  
John T. McDevitt
Keyword(s):  
Electron Microscopy ◽  
Carbon Dioxide ◽  
High Temperature ◽  
High Temperature Superconductor ◽  
Relative Reactivity ◽  
Complete Understanding ◽  
High Tc ◽  
X Ray ◽  
The Common ◽  
Scanning Electron

ABSTRACTMany of the high temperature superconductor phases degrade rapidly when in the presence of water, acids, carbon dioxide or carbon monoxide. In order to foster more rapid developments in the area of high-Tc research, it will be necessary to acquire a more complete understanding of the surface chemistry of these superconducting materials. In this paper, the relative reactivity of the common cuprate phases toward water is reported. X-ray powder diffraction and scanning electron microscopy measurements are utilized here to establish the reactivity trends.

scholarly journals Slip of the T tube within the common bile duct: A little known complication of the T tube drainage

2005 ◽  
Vol 133 (3-4) ◽  
pp. 138-141
Author(s):  
Radoje Colovic ◽  
Vladimir Radak ◽  
Nikica Grubor ◽  
Slavko Matic
Keyword(s):  
Bile Duct ◽  
Common Bile Duct ◽  
Tube Drainage ◽  
X Ray ◽  
Abdominal Drain ◽  
T Tube ◽  
Tube Position ◽  
Bile Drainage ◽  
The Common ◽  
The Right

Complications related to the T tube drainage of the common bile duct are not uncommon. Some, like dislocations of the T tube out of the common bile duct, could be very serious, particularly if developed during the first few days after surgery, when the abdominal drain in the subhepatic space had been already removed. Then, an emergency reoperation might be necessary. The slip of the T tube upwards or downwards inside the common bile duct is not so rare. Fortunately, it is less dangerous and can usually be resolved without reoperation. It takes place several days after surgery, followed by the right subcostal pain, occasionally with temperature, rise of the bilirubin and with decrease or complete cessation of the bile drainage through the T tube. The diagnosis can be made only on the basis of T tube cholangiography. The re-establishment of the proper T tube position must be done under X-ray visualization. Seven cases of the T tube slip within the common bile duct, its clinical presentation, diagnosis and method of repositioning were presented. Possible mechanism of complication was described. As far as we know, the complications have not been described by other authors.

scholarly journals Remote control of neural function by X-ray-induced scintillation

2019 ◽  
Author(s):  
Takanori Matsubara ◽  
Takayuki Yanagida ◽  
Noriaki Kawaguchi ◽  
Takashi Nakano ◽  
Junichiro Yoshimoto ◽  
...  
Keyword(s):  
Dopamine Neurons ◽  
Neural Function ◽  
X Rays ◽  
Cellular Functions ◽  
X Ray ◽  
Functional Studies ◽  
Clinical Dose ◽  
Visible Luminescence ◽  
Midbrain Dopamine ◽  
The Brain

Scintillators emit visible luminescence when irradiated with X-rays. Given the unlimited tissue penetration of X-rays, the employment of scintillators could enable remote optogenetic control of neural functions at any depth of the brain. Here we show that a yellow-emitting inorganic scintillator, Ce-doped Gd3(Al,Ga)5O12 (Ce:GAGG), could effectively activate red-shifted excitatory and inhibitory opsins, ChRmine and GtACR1, respectively. Using injectable Ce:GAGG microparticles, we successfully activated and inhibited midbrain dopamine neurons in freely moving mice by X-ray irradiation, producing bidirectional modulation of place preference behavior. Ce:GAGG microparticles were non-cytotoxic and biocompatible, allowing for chronic implantation. Pulsed X-ray irradiation at a clinical dose level was sufficient to elicit behavioral changes without reducing the number of radiosensitive cells in the brain and bone marrow. Thus, scintillator-mediated optogenetics enables less invasive, wireless control of cellular functions at any tissue depth in living animals, expanding X-ray applications to functional studies of biology and medicine.

scholarly journals Crystal structure of SARS-CoV-2 main protease in complex with a Chinese herb inhibitor shikonin

2020 ◽  
Author(s):  
Jian Li ◽  
Xuelan Zhou ◽  
Yan Zhang ◽  
Fanglin Zhong ◽  
Cheng Lin ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Conformational Changes ◽  
Drug Targets ◽  
Chinese Herb ◽  
Binding Modes ◽  
High Potency ◽  
Main Protease ◽  
Covalent Inhibitors ◽  
Catalytic Dyad ◽  
Important Drug

AbstractMain protease (Mpro, also known as 3CLpro) has a major role in the replication of coronavirus life cycle and is one of the most important drug targets for anticoronavirus agents. Here we report the crystal structure of main protease of SARS-CoV-2 bound to a previously identified Chinese herb inhibitor shikonin at 2.45 angstrom resolution. Although the structure revealed here shares similar overall structure with other published structures, there are several key differences which highlight potential features that could be exploited. The catalytic dyad His41-Cys145 undergoes dramatic conformational changes, and the structure reveals an unusual arrangement of oxyanion loop stabilized by the substrate. Binding to shikonin and binding of covalent inhibitors show different binding modes, suggesting a diversity in inhibitor binding. As we learn more about different binding modes and their structure-function relationships, it is probable that we can design more effective and specific drugs with high potency that can serve as effect SARS-CoV-2 anti-viral agents.

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