Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pathways corresponding to the conformational change in nitrogen regulatory protein C are calculated using the CHARMM19 force field with an implicit solvation model. Our analysis employs the discrete path sampling approach to grow a database of local minima and transition states from the potential energy surface that contains kinetically relevant pathways. The pathways with the largest contribution to the phenomenological two-state rate constants are found to exhibit a number of structural features that agree with experimental observations. Further details of the calculated pathways for conformational change may therefore provide useful predictions of how this large-scale motion is achieved.
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PMID:Pathways for conformational change in nitrogen regulatory protein C from discrete path sampling. 1824 95

An approach to find transition pathways in complex systems is presented. The method, which is related to the string method in collective variables of Maragliano et al. (J. Chem. Phys. 2006, 125, 024106), is conceptually simple and straightforward to implement. It consists of refining a putative transition path in the multidimensional space supported by a set of collective variables using the average dynamic drift of those variables. This drift is estimated on-the-fly via swarms of short unbiased trajectories started at different points along the path. Successive iterations of this algorithm, which can be naturally distributed over many computer nodes with negligible interprocessor communication, refine an initial trial path toward the most probable transition path (MPTP) between two stable basins. The method is first tested by determining the pathway for the C7eq to C7ax transition in an all-atom model of the alanine dipeptide in vacuum, which has been studied previously with the string method in collective variables. A transition path is found with a committor distribution peaked at 1/2 near the free energy maximum, in accord with previous results. Last, the method is applied to the allosteric conformational change in the nitrogen regulatory protein C (NtrC), represented here with a two-state elastic network model. Even though more than 550 collective variables are used to describe the conformational change, the path converges rapidly. Again, the committor distribution is found to be peaked around 1/2 near the free energy maximum between the two stable states, confirming that a genuine transition state has been localized in this complex multidimensional system.
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PMID:Finding transition pathways using the string method with swarms of trajectories. 1829 Jun 41

Receiver domains are key molecular switches in bacterial signaling. Structural studies have shown that the receiver domain of the nitrogen regulatory protein C (NtrC) exists in a conformational equilibrium encompassing both inactive and active states, with phosphorylation of Asp54 allosterically shifting the equilibrium towards the active state. To analyze dynamical fluctuations and correlations in NtrC as it undergoes activation, we have applied a coarse-grained dynamics algorithm using elastic network models. Normal mode analysis reveals possible dynamical pathways for the transition of NtrC from the inactive state to the active state. The diagonalized correlation between the inactive and the active (phosphorylated) state shows that most correlated motions occur around the active site of Asp54 and in the region Thr82 to Tyr101. This indicates a coupled correlation of dynamics in the "Thr82-Tyr101" motion. With phosphorylation inducing significant flexibility changes around the active site and alpha3 and alpha4 helices, we find that this activation makes the active-site region and the loops of alpha3/beta4 and alpha4/beta5 more stable. This means that phosphorylation entropically favors the receiver domain in its active state, and the induced conformational changes occur in an allosteric manner. Analyses of the local flexibility and long-range correlated motion also suggest a dynamics criterion for determining the allosteric cooperativity of NtrC, and may be applicable to other proteins.
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PMID:Coarse-grained dynamics of the receiver domain of NtrC: fluctuations, correlations and implications for allosteric cooperativity. 1841 61

Perinatal hypoxia-ischemia remains the single most important cause of brain injury in the newborn, leading to death or lifelong sequelae. White matter injuries in newborn infants have long-term effects on physical, visual, motor, sensory, cognitive and social development in human infants. There is no known cure for neonatal hypoxic ischemic encephalopathy (NHIE). Activated protein C has potent anticoagulant activity due to its ability to inactivate factor Va and VIIIa. APC is the first effective biological therapy approved for the treatment of severe sepsis. Although APC is well defined as a physiological anticoagulant, emerging data suggest that it also has cytoprotective, anti-inflammatory and antiapoptotic properties. APC has been shown to provide neuroprotection in ischemic brain and spinal cord injury. Here, we propose that APC, which modulates many of these processes, may represent a promising therapeutic agent for NHIE. Seven days old Wistar Albino rat pups have been used in the study (n=42). Experimental groups in the study were: sham-operated group, APC treated group, and vehicle treated group. In hypoxia-ischemia groups, the left common carotid artery was ligated permanently on the seventh postnatal day. Two hours after the procedure, hypoxia (92% nitrogen and 8% oxygen) was applied for 2.5 h. APC were injected (intraperitoneally; i.p.) as a single dose immediately after the hypoxia period. Brain nitrite levels, neuronal cell death, and apoptosis were evaluated in both hemispheres 72 h after the hypoxic-ischemic insult. Histopathological evaluation demonstrated that APC significantly diminished the number of "apoptotic cells" in the hippocampal CA1, CA2, CA3 and gyrus dentatus regions in both hemispheres. APC treatment significantly reduced "apoptotic cell death" in both hemispheres, when compared with vehicle treated group. APC significantly preserved the number of neurons CA1, CA3 regions of the hippocampus, when compared with vehicle treated group. Our results showed that hypoxic-ischemic injury caused a significant increase in NO production. The APC-treated animals were reduced brain nitrite levels in carotid ligated hemispheres. To our knowledge, this is the first study that demonstrates a protective effect of the APC against hypoxia-ischemia in the developing brain.
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PMID:Effects of activated protein C on neonatal hypoxic ischemic brain injury. 1842 Jan 81

Dual-function hybrid material U1 was designed for simultaneous chromofluorogenic detection and removal of Hg(2+) in an aqueous environment. Mesoporous material UVM-7 (MCM41 type) with homogeneously distributed pores of about 2-3 nm in size, a large specific surface area exceeding 1000 m(2) g(-1), and nanoscale particles was used as an inorganic support. The mesoporous solid is decorated with thiol groups that were treated with squaraine dye III to give a 2,4-bis(4-dialkylaminophenyl)-3-hydroxy-4-alkylsulfanylcyclobut-2-enone (APC) derivative that is covalently anchored to the inorganic silica matrix. The solid was characterised by various techniques including X-ray diffraction, transmission electron microscopy, Raman spectroscopy, and nitrogen adsorption. This hybrid solid is the chemodosimeter for Hg(2+) detection. Hg(2+) reacts with the APC fragment in U1 with release of the squaraine dye into the solution, which turns deep blue and fluoresces strongly. Naked-eye Hg(2+) detection is thus accomplished in an easy-to-use procedure. In contrast, U1 remains silent in the presence of other thiophilic transition metal ions, alkali and alkaline earth metal ions, or anions ubiquitously present in water such as chloride, carbonate, sulfate, and phosphate. Material U1 acts not only as chemodosimeter that signals the presence of Hg(2+) down to parts-per-billion concentrations, but at the same time is also an excellent adsorbent for the removal of mercury cations from aqueous solutions. The amount of adsorbed mercury ranges from 0.7 to 1.7 mmol g(-1), depending on the degree of functionalisation. In addition, hybrid material U1 can be regenerated for both sensing and removal purposes. As far as we know, U1 is the first example of a promising new class of polyfunctional hybrid supports that can be used as both remediation and alarm systems by selective signalling and removal of target species of environmental importance. Model compounds based on silica gel (G1), fumed silica (F1), and micrometre-sized MCM-41 scaffolds (M1) were also prepared and studied for comparative purposes.
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PMID:A mesoporous 3D hybrid material with dual functionality for Hg2+ detection and adsorption. 1866 95

Hydrogen uptake protein regulator (HupR) is a member of the nitrogen regulatory protein C (NtrC) family of response regulators. These proteins activate transcription by RNA polymerase (RNAP) in response to a change in environment. This change is detected through the phosphorylation of their receiver domain as part of a two-component signalling pathway. HupR is an unusual member of this family as it activates transcription when unphosphorylated, and transcription is inhibited by phosphorylation. Also, HupR activates transcription through the more general sigma(70) transcription initiation factor, which does not require activation by ATPase, in contrast to other NtrC family members that utilise sigma(54). Hence, its mode of action is expected to be different from those of the more conventional NtrC family members. We have determined the structures of the unphosphorylated N-terminal receiver domain of wild-type HupR, the mutant HupR(D55E)(N) (which cannot be phosphorylated and down-regulated), and HupR in the presence of the phosphorylation mimic BeF(3)(-). The structures show a typical response regulator fold organised as a dimer whose interface involves alpha4-beta5-alpha5 elements. The interactions across the interface are slightly different between apo and phospho mimics, and these reflect a rearrangement of key conserved residues around the active site aspartate that have been implicated in domain activation in other receiver domain proteins. We also show that the wild-type HupR receiver domain forms a weak dimer in solution, which is strengthened in the presence of the phosphorylation mimic BeF(3)(-). The results indicate many features similar to those that have been observed in other systems, including NtrC (where phosphorylation is activatory), and indicate that recognition properties, which allow HupR to be active in the absence of phosphorylation, lie in the transmission of phosphorylation signals through the linker region to the other domains of the protein.
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PMID:The HupR receiver domain crystal structure in its nonphospho and inhibitory phospho states. 1897 59

Streptococcus mutans, a biofilm-forming Gram-positive bacterium that resides in the human oral cavity, is considered to be the primary aetiological agent of human dental caries. A cell-envelope stress-sensing histidine kinase, LiaS, is considered to be important for expression of virulence factors such as glucan-binding protein C and mutacin production. In this study, a liaS mutant was subjected to phenotypic microarray (PM) analysis of about 2000 phenotypes, including utilization of various carbon, nitrogen, phosphate and sulfur sources; osmolytes; metabolic inhibitors; and susceptibility to toxic compounds, including several types of antibiotics. Compared to the parental strain UA159, the liaS mutant strain (IBS148) was more tolerant to various inhibitors that target protein synthesis, DNA synthesis and cell-wall biosynthesis. Some of the key findings of the PM analysis were confirmed in independent growth studies and by using antibiotic discs and E-test strips for susceptibility testing.
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PMID:A phenotypic microarray analysis of a Streptococcus mutans liaS mutant. 1911 47

The present study was attempted to assess the prophylactic and the therapeutic effect of human recombinant activated protein C (APC; drotrecogin-alpha, activated) in experimental heat stroke. Anesthetized rats were divided into two groups and given vehicle solution 1 h before the start or immediately after the termination of heat stress (isotonic sodium chloride solution, 2 mL kg(-1) of body weight, i.v.) or APC (1-10 mg in 2 mL of isotonic sodium chloride solution per kilogram of body weight, i.v.). They were exposed to ambient temperature of 40 degrees C for 100 min to induce heat stroke. When the vehicle-pretreated rats underwent heat stress, their survival time values were found to be 57 to 71 min. Pretreatment or treatment with APC significantly increased survival time (122-221 min). All vehicle-pretreated heat stroke animals displayed systemic inflammation (evidenced by increased TNF-alpha, IL-1alpha, and IL-6) and activated coagulation (evidenced by increased levels of activated partial thromboplastin time, prothrombin time, and D-dimer and decreased levels of both platelet count and protein C). Biochemical assay also revealed that both renal and hepatic dysfunction (e.g., increased plasma levels of blood urea nitrogen, creatinine, adenine aminotransferase, aspartate aminotransferase, and alkaline phosphatase) were noted during heat stroke. A significant decrease in both cerebral blood flow and partial pressure of oxygen in hypothalamus were also observed in vehicle-pretreated heat stroke animals. These heat stroke reactions were all significantly reduced by pretreatment or treatment with human recombinant APC. The results indicate that human recombinant APC can be used as a prophylactic and a therapeutic agent for experimental heat stroke by ameliorating systemic inflammation, hypercoagulable state, and multiple organ dysfunction.
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PMID:Activated protein C can be used as a prophylactic as well as a therapeutic agent for heat stroke in rodents. 1929 93

Multiple self-guided Langevin dynamics (SGLD) simulations were performed to examine structural and dynamical properties of the receiver domain of nitrogen regulatory protein C (NtrC(r)). SGLD and MD simulations of the phosphorylated active form structure suggest a mostly stable but broad structural ensemble of this protein. The finite difference Poisson-Boltzmann calculations of the pK(a) values of the active site residues suggest an increase in the pK(a) of His-84 on phosphorylation of Asp-54. In SGLD simulations of the phosphorylated active form with charged His-84, the average position of the regulatory helix alpha4 is found closer to the starting structure than in simulations with the neutral His-84. To model the transition pathway, the phosphate group was removed from the simulations. After 7 ns of simulations, the regulatory helix alpha4 was found approximately halfway between positions in the NMR structures of the active and inactive forms. Removal of the phosphate group stimulated loss of helix alpha4, suggesting that the pathway of conformational transition may involve partial unfolding mechanism. The study illustrates the potential utility of the SGLD method in studies of the coupling between ligand binding and conformational transitions.
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PMID:Self-guided Langevin dynamics study of regulatory interactions in NtrC. 1938 96

An improved and simplified version of the finite temperature string (FTS) method [W. E, W. Ren, and E. Vanden-Eijnden, J. Phys. Chem. B 109, 6688 (2005)] is proposed. Like the original approach, the new method is a scheme to calculate the principal curves associated with the Boltzmann-Gibbs probability distribution of the system, i.e., the curves which are such that their intersection with the hyperplanes perpendicular to themselves coincides with the expected position of the system in these planes (where perpendicular is understood with respect to the appropriate metric). Unlike more standard paths such as the minimum energy path or the minimum free energy path, the location of the principal curve depends on global features of the energy or the free energy landscapes and thereby may remain appropriate in situations where the landscape is rough on the thermal energy scale and/or entropic effects related to the width of the reaction channels matter. Instead of using constrained sampling in hyperplanes as in the original FTS, the new method calculates the principal curve via sampling in the Voronoi tessellation whose generating points are the discretization points along this curve. As shown here, this modification results in greater algorithmic simplicity. As a by-product, it also gives the free energy associated with the Voronoi tessellation. The new method can be applied both in the original Cartesian space of the system or in a set of collective variables. We illustrate FTS on test-case examples and apply it to the study of conformational transitions of the nitrogen regulatory protein C receiver domain using an elastic network model and to the isomerization of solvated alanine dipeptide.
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PMID:Revisiting the finite temperature string method for the calculation of reaction tubes and free energies. 1946 17


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