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1
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Computer modeling studies of the structural role of NADPH binding to active site mutants of human dihydrofolate reductase in complex with piritrexim.

100%
Nowak W., Cody V., Wojtczak A.
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2001
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vol. 48
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issue 4
903-916
EN
Dihydrofolate reductase (DHFR, EC 1.5.1.3) is one of the enzymes active in the folate cycle which plays an important role in DNA synthesis. Inhibition of DHFR is a key element in the treatment of many diseases, including cancer and AIDS related infections. A search for new selective inhibitors is motivated by the resistance to common drugs observed in the course of treatment. In this paper, results of a detailed computer analysis of human DHFR interactions with the lipophilic inhibitor piritrexim (PTX) are presented. It was found that the NADPH cofactor contributes 30% of the total PTX-enzyme interaction energy. Substitution of the highly conserved Glu30 with alanine does not lead to the release of the inhibitor from the hDHFR pocket. The important L22F point mutation does affect PTX orientation but does not change the binding energy. Simulations of the dynamics of binary hDHFR-TX complexes were performed with the use of Extensible Systematic Force Field (ESFF) and the results indicate structural changes in the enzyme induced by NADPH binding.
2
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Unusual potassium-oxalate coordination in the two-dimensional trimetallic [CoCl(NH3)5][KCr(C2O4)3]·0.5H2O complex

100%
Wrzeszcz G., Wojtczak A., Zawadzka M.
Open Chemistry
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2014
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vol. 12
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issue 6
652-658
EN
A new heterometallic compound, [CoCl(NH3)5][KCr(C2O4)3]·0.5H2O (1), has been synthesized and characterized by elemental analysis, IR and electronic spectra, thermal analysis, variable temperature magnetic susceptibility measurements, and single crystal X-ray diffraction. Compound 1 consists of two-dimensional [{KCr(C2O4)3}n]2n− layers, [CoCl(NH3)5]2+ ions and water molecules. Within the 2-D layer, three different types of oxalate coordination modes are present. Each K cation is coordinated by eight oxygen atoms from oxalate groups and also weakly interacts with the ninth oxygen atom. The extensive network of hydrogen bond is formed between the [KCr(C2O4)3]2− layer and the [CoCl(NH3)5]2+ ions. These interactions involve all hydrogen atoms of ammonia ligads and water molecule.
3
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Role of pro-inflammatory cytokines of pancreatic islets and prospects of elaboration of new methods for the diabetes treatment

100%
Cieślak M., Wojtczak A., Cieślak M.
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2015
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vol. 62
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issue 1
15-21
EN
Several relations between cytokines and pathogenesis of diabetes are reviewed. In type 1 and type 2 diabetes an increased synthesis is observed and as well as the release of pro-inflammatory cytokines, which cause the damage of pancreatic islet cells and, in type 2 diabetes, the development of the insulin resistance. That process results in the disturbed balance between pro-inflammatory and protective cytokines. Pro-inflammatory cytokines such as interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), as well as recently discovered pancreatic derived factor PANDER are involved in the apoptosis of pancreatic β-cells. Inside β-cells, cytokines activate different metabolic pathways leading to the cell death. IL-1β activates the mitogen-activated protein kinases (MAPK), affects the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activates the inducible nitric oxide synthase (iNOS). TNF-α and IFN-γ in a synergic way activate calcium channels, what leads to the mitochondrial dysfunction and activation of caspases. Neutralization of pro-inflammatory cytokines, especially interleukin 1β with the IL-1 receptor antagonist (IL-1Ra) and/or IL-1β antibodies might cause the extinction of the inflammatory process of pancreatic islets, and consequently normalize concentration of glucose in blood and decrease the insulin resistance. In type 1 diabetes interleukin-6 participates in regulation of balance between Th17 and regulatory T cells. In type 2 diabetes and obesity, the long-duration increase of IL-6 concentration in blood above 5 pg/ml leads to the chronic and permanent increase in expression of SOCS3, contributing to the increase in the insulin resistance in cells of the skeletal muscles, liver and adipose tissue.
4
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Comparison of binding interactions of dibromoflavonoids with transthyretin.

100%
Muzioł T., Cody V., Wojtczak A.
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2001
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vol. 48
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issue 4
885-892
EN
The crystal structure of rat transthyretin (rTTR) complex with the dibromoflavone EMD21388 was determined to 2.3 Å resolution and refined to R = 0.203 and Rfree = 0.288. Two different orientations of EMD21388, which differ in the channel penetration by 1.6 Å, were found in the A/C binding site of rTTR. The single ligand position observed in the B/D site is intermediate between the two positions found in the A/C site. The position of the dibromoflavone in the B/D site is similar to that reported for dibromoaurone in human TTR. The bromine atoms of EMD21388 form strong interactions in the P3 and P3' pockets of rTTR. Due to the different molecular architectures of both ligands, dibromoflavone forms only one interaction with Lys-15 near the channel entrance, while direct interactions with the pair of Lys-15 were reported for dibromoaurone. The C3* methyl group of EMD21388 mediates the bridging interactions between two TTR subunits in the P2 pockets. The interactions of the O2* hydroxyl group of dibromoaurone with the Thr-119 side chain in the P3 pockets are not matched by similar interactions in EMD21388. Both these alternative interactions can explain the competitive binding of 3',5'-dibromoflavonoids to transthyretin.
5
Content available remote

Relationship between the induction of inflammatory processes and infectious diseases in patients with ischemic stroke

100%
Cieślak M., Wojtczak A., Cieślak M.
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2013
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vol. 60
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issue 3
345-349
EN
Pro-inflammatory cytokines participate in the induction of ischemic stroke. So far, their participation in the cerebral ischemia was proven for the tumor necrosis factor TNF-α, interleukin-1 (IL-1), and interleukin-6 (IL-6). The release of the pro-inflammatory cytokines into the extracellular space causes the enlargement of the brain damage region, and consequently increases the neurological deficit and negatively affects the survival rate prognoses. That is confirmed by the increased concentration of pro-inflammatory cytokines in blood and the cerebrospinal fluid of patients with brain stroke, as well as by the research on the induced/experimental cerebral ischemia in animals. The pro-inflammatory cytokines participate in the migration of the reactive T lymphocytes to the regions of brain ischemia where they enhance the nerve tissue damage by down-regulation of microcirculation, induce the pro-thrombotic processes and release other neurotoxic cytokines. Also, in the early stage of cerebral ischemia, cytokines activate the axis hypothalamus-pituitary gland-adrenal cortex and increase the cortisol concentration in blood, what results in the decreased resistance to infectious diseases. Administration of the inhibitor of the interleukin-1 receptor (IL-1Ra) inhibits the inflammatory processes in the region of brain ischemia, and subsequently improves the prognosis for the size of the neurological deficit and the survival rate, as well as resistance to infectious diseases.
6
Content available remote

Structural basis of negative cooperativity in transthyretin

100%
Neumann P., Cody V., Wojtczak A.
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2001
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vol. 48
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issue 4
867-875
EN
A comparison of the AC and BD binding sites of transthyretin (TTR) was made in terms of the interatomic distances between the Cα atoms of equivalent amino acids, measured across the tetramer channel in each binding site. The comparison of the channel diameter for apo TTR from different sources revealed that in the unliganded transthyretin tetramers the distances between the A, D and H β-strands are consistently larger, while the distances between the G β-strands are smaller in one site than in the other. These differences might be described to have a 'wave' character. An analogous analysis performed for transthyretin complexes reveals that the shape of the plot is similar, although the amplitudes of the changes are smaller. The analysis leads us to a model of the changes in the binding sites caused by ligand binding. The sequence of events includes ligand binding in the first site, followed by a slight collapse of this site and concomitant opening of the second site, binding of the second molecule and collapse of the second site. The following opening of the first, already occupied site upon ligand binding in the second site is smaller because of the bridging interactions already formed by the first ligand. This explains the negative cooperativity (NC) effect observed for many ligands in transthyretin.
7
Content available remote

Crystal structure of rat transthyretin at 2.5 Å resolution: First report on a unique tetrameric structure

98%
Wojtczak A.
Acta Biochimica Polonica
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1997
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vol. 44
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issue 3
505-517
8
Content available remote

Complex of rat transthyretin with tetraiodothyroacetic acid refined at 2.1 and 1.8 Å resolution.

88%
Muzioł T., Cody V., Luft J. R., Pangborn W., Wojtczak A.
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2001
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vol. 48
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issue 4
877-884
EN
The crystal structure of rat transthyretin (rTTR) complex with 3,5,3' ,5' -tetraiodothyroacetic acid (T4Ac) was determined at 1.8 Å resolution with low temperature synchrotron data collected at CHESS. The structure was refined to R = 0.207 and Rfree= 0.24 with the use of 8-1.8 Å data. The additional 8000 reflections from the incomplete 2.1-1.8 data shell, included in the refinement, reduced the Rfree index by 1.3%. Structure comparison with the model refined against the complete 8-2.1 Å data revealed no differences in the ligand orientation and the conformation of the polypeptide chain in the core regions. However, the high-resolution data included in the refinement improved the model in the flexible regions poorly defined with the lower resolution data. Also additional sixteen water molecules were found in the difference map calculated with the extended data. The structure revealed both forward and reverse binding of tetraiodothyroacetic acid in one binding site and two modes of forward ligand binding in the second site, with the phenolic iodine atoms occupying different sets of the halogen binding pockets.
9
Content available remote

Modeling studies of potato nucleoside triphosphate diphosphohydrolase NTPDase1: an insight into the catalytic mechanism

88%
Kozakiewicz A., Neumann P., Banach M., Komoszyński M., Wojtczak A.
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2008
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vol. 55
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issue 1
141-150
EN
Nucleoside triphosphate diphosphohydrolase - NTPDase1 (apyrase, EC 3.6.1.5) was modeled based on sequence homology. The single polypeptide chain of apyrase is folded into two domains. The putative catalytic site with the apyrase conserved regions (ACR 1-5) is located between these two domains. Modeling confirmed that apyrase belongs to the actin superfamily of proteins. The amino acids interacting with the nucleoside triphosphate substrate and probably involved in the catalyzed hydrolysis were identified. The proposed two-step catalytic mechanism of hydrolysis involves Thr127 and Thr55 as potential nucleophilic factors responsible for the cleavage of the Pγ and Pβ anhydride bonds, respectively. Their action seems to be assisted by Glu170 and Glu78 residues, respectively. The presence of two nucleophiles in the active site of apyrase explains the differences in the hydrolytic activity between apyrases and other enzymes belonging to the NTPDase family.
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