scholarly journals Evolution of cation binding in the active sites of P-loop nucleoside triphosphatases

2018 ◽  
Author(s):  
Daria N. Shalaeva ◽  
Dmitry A. Cherepanov ◽  
Michael Y. Galperin ◽  
Armen Y. Mulkidjanian
Keyword(s):  
Active Sites ◽  
Atp Hydrolysis ◽  
Md Simulations ◽  
Cation Binding ◽  
Potassium Ions ◽  
Sodium Ions ◽  
Ammonium Ions ◽  
Phosphate Chain ◽  
Comparative Structure ◽  
Phosphate Groups

AbstractThe activity of cellular nucleoside triphosphatases (NTPases) must be tightly controlled to prevent spontaneous ATP hydrolysis leading to cell death. While most P-loop NTPases require activation by arginine or lysine fingers, some of the apparently ancestral ones are, instead, activated by potassium ions, but not by sodium ions. We combined comparative structure analysis of P-loop NTPases of various classes with molecular dynamics (MD) simulations of Mg-ATP complexes in water and in the presence of potassium, sodium, or ammonium ions. In all analyzed structures, the conserved P-loop motif keeps the triphosphate chains of enzyme-bound NTPs in an extended, catalytically prone conformation, similar to that attained by ATP in water in the presence of potassium or ammonium ions bound between alpha- and gamma-phosphate groups. The smaller sodium ions could not reach both alpha- and gamma-phosphates of a protein-bound extended phosphate chain and therefore are unable to activate most potassium-dependent P-loop NTPases.

scholarly journals Evolution of cation binding in the active sites of P-loop nucleoside triphosphatases in relation to the basic catalytic mechanism

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Daria N Shalaeva ◽  
Dmitry A Cherepanov ◽  
Michael Y Galperin ◽  
Andrey V Golovin ◽  
Armen Y Mulkidjanian
Keyword(s):  
Active Sites ◽  
Catalytic Mechanism ◽  
Md Simulations ◽  
Basic Mechanism ◽  
Cation Binding ◽  
Activation Mechanism ◽  
Potassium Ions ◽  
Ammonium Ions ◽  
Mechanism Of Hydrolysis ◽  
Comparative Structure

The ubiquitous P-loop fold nucleoside triphosphatases (NTPases) are typically activated by an arginine or lysine ‘finger’. Some of the apparently ancestral NTPases are, instead, activated by potassium ions. To clarify the activation mechanism, we combined comparative structure analysis with molecular dynamics (MD) simulations of Mg-ATP and Mg-GTP complexes in water and in the presence of potassium, sodium, or ammonium ions. In all analyzed structures of diverse P-loop NTPases, the conserved P-loop motif keeps the triphosphate chain of bound NTPs (or their analogs) in an extended, catalytically prone conformation, similar to that imposed on NTPs in water by potassium or ammonium ions. MD simulations of potassium-dependent GTPase MnmE showed that linking of alpha- and gamma phosphates by the activating potassium ion led to the rotation of the gamma-phosphate group yielding an almost eclipsed, catalytically productive conformation of the triphosphate chain, which could represent the basic mechanism of hydrolysis by P-loop NTPases.

scholarly journals Comparative analysis of active sites in P-loop nucleoside triphosphatases suggests an ancestral activation mechanism

2018 ◽  
Author(s):  
Daria N. Shalaeva ◽  
Dmitry A. Cherepanov ◽  
Michael Y. Galperin ◽  
Armen Y. Mulkidjanian
Keyword(s):  
Active Sites ◽  
Catalytic Mechanism ◽  
Md Simulations ◽  
Activation Mechanism ◽  
Sequence Motifs ◽  
Backbone Amide ◽  
Comparative Structure ◽  
Combined Structure ◽  
Phosphate Groups ◽  
Positively Charged

AbstractP-loop nucleoside triphosphatases (NTPases) share common Walker A (P-loop) and Walker B sequence motifs and depend on activating moieties (Arg or Lys fingers or a K+ ion). In search for a common catalytic mechanism, we combined structure comparisons of active sites in major classes of P-loop NTPases with molecular dynamics (MD) simulations of the Ras GTPase, a well-studied oncoprotein. Comparative structure analysis showed that positively charged activating moieties interact with gamma-phosphate groups of NTP substrates in all major classes of P-loop NTPases. In MD simulations, interaction of the activating Arg finger with the Mg-GTP-Ras complex led to the rotation of the gamma-phosphate group by 40 degrees enabling its interaction with the backbone amide group of Gly13. In all analyzed structures, the residue that corresponds to Gly13 of Ras was in a position to stabilize gamma-phosphate after its rotation, suggesting a common ancestral activation mechanism within the entire superfamily.

Ground water quality of selected areas of Punjab and Sind Provinces, Pakistan: Chemical and microbiological aspects

2019 ◽  
Author(s):  
Chem Int
Keyword(s):  
Ionic Concentration ◽  
Chloride Ions ◽  
Potassium Ions ◽  
Ammonium Ions ◽  
High Concentration ◽  
Phosphate Ions ◽  
Sodium Magnesium ◽  
Very High ◽  
Microbiological Aspects

The assessment of groundwater is essential for the estimation of suitability of water for safe use. An attempt has been made to study the groundwater of selected areas of Punjab (Sheikhupura & Sahiwal) and Sindh (Sindh, Jawar Dharki and Dharki), Pakistan. The results indicate that pH, color and odor were all within limits of WHO that is pH ranges 6.5–8.5, colorless and odorless, respectively. The high values of suspended solids were observed in the Sindh-1 and Dharki samples. Microbiologically only Sahiwal and Jawar Dharki were found fit for drinking purpose. Trace metals analysis of Sheikhupura-1 and Sindh-1 showed that values do not fall within limits of WHO for Iron. The ionic concentration analysis showed that high bicarbonate (HCO3-), ions are present in the samples of Sahiwal and Dharki; Sindh-1 and Jawar Dharki samples showed very high concentration for chloride ions, all samples were satisfactory level for sulphate (SO42-), sodium, magnesium and phosphate ions except samples of Sindh-1 and Jawar Dharki. High concentration of calcium and potassium ions was observed in samples of Sindh-1, while all other samples were found fit for drinking purposes in respect of nitrate, nitrite and ammonium ions. The high concentration of Fluoride was found only in Sheikhupura-2 samples.

ИЗУЧЕНИЕ СТРУКТУРЫ ДНК В ПЛЕНКАХ МЕТОДОМ ИК-ФУРЬЕ-СПЕКТРОСКОПИИ

2020 ◽  
Vol 65 (6) ◽  
pp. 1058-1064
Author(s):  
С.В. Пастон ◽  
◽  
А.М. Поляничко ◽  
О.В. Шуленина ◽  
Д.Н. Осинникова ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Hydration Shell ◽  
Aqueous Environment ◽  
Ir Absorption ◽  
Sodium Ions ◽  
High Molecular Weight Dna ◽  
Dna Hydration ◽  
Na Ions ◽  
Phosphate Groups ◽  
Dna Film

The aqueous environment and ionic surrounding are the most important factors determining the conformation of DNA and its functioning in the cell. The specificity of the interaction between DNA and cations is especially pronounced with a decrease in water activity. In this work, we studied the B-A transition in high molecular weight DNA with a decrease of humidity in the film with different contents of Na+ ions using FTIR spectroscopy. The IR spectrum of DNA is not only very sensitive to the state of its secondary structure, but also allows us to estimate the amount of water bound to DNA. Upon dehydration of the DNA film, changes characteristic of the B-A transition were observed in the IR absorption spectrum. Using thermogravimetric analysis, it was shown that the degree of DNA hydration reaches the saturation level at a relative humidity of 60% and decreases slightly upon further drying. It has been established that with increasing Na+ concentration, the amount of water strongly bound to DNA decreases. Along with it, sodium ions destroy the hydration shell of DNA and are able to interact directly with phosphate groups.

Sodium and Potassium Fluxes in the Abdominal Nerve Cord of the Cockroach, Periplaneta Americana L

1961 ◽  
Vol 38 (2) ◽  
pp. 315-322
Author(s):  
J. E. TREHERNE
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Nerve Cord ◽  
Periplaneta Americana ◽  
Unit Area ◽  
Potassium Ions ◽  
Sodium Ions ◽  
Nerve Sheath ◽  
The Central Nervous System ◽  
Sodium And Potassium

1. The influx of sodium and potassium ions into the central nervous system of Periplaneta americana has been studied by measuring the increase in radioactivity within the abdominal nerve cord following the injection of 24NA and 42K. into the haemolymph. 2. The calculated influx of sodium ions was approximately 320 mM./l. of nerve cord water/hr. and of potassium ions was 312 mM./l. of nerve cord water/hr. These values are very approximately equivalent to an influx per unit area of nerve cord surface of 13.9 x 10-2 M cm. -2 sec.-1 for sodium and 13.5 x 10-12 M cm. -2 sec.-1 for potassium ions. 3. The relatively rapid influxes of these ions are discussed in relation to the postulated function of the nerve sheath as a diffusion barrier. It is suggested that a dynamic steady state rather than a static impermeability must exist across the sheath surrounding the central nervous system in this insect.

scholarly journals Insight into Inhibitor Binding in the Eukaryotic Proteasome: Computations of the 20S CP

2018 ◽  
Vol 19 (12) ◽  
pp. 3858
Author(s):  
Milan Hodošček ◽  
Nadia Elghobashi-Meinhardt
Keyword(s):  
Electrostatic Interactions ◽  
Active Sites ◽  
Sampling Period ◽  
Md Simulations ◽  
Structural Features ◽  
Relaxation Dynamics ◽  
Inhibitor Binding ◽  
Computational Analyses ◽  
Insight Into ◽  
Proteolytic Chamber

A combination of molecular dynamics (MD) simulations and computational analyses uncovers structural features that may influence substrate passage and exposure to the active sites within the proteolytic chamber of the 20S proteasome core particle (CP). MD simulations of the CP reveal relaxation dynamics in which the CP slowly contracts over the 54 ns sampling period. MD simulations of the SyringolinA (SylA) inhibitor within the proteolytic B 1 ring chamber of the CP indicate that favorable van der Waals and electrostatic interactions account for the predominant association of the inhibitor with the walls of the proteolytic chamber. The time scale required for the inhibitor to travel from the center of the proteolytic chamber to the chamber wall is on the order of 4 ns, accompanied by an average energetic stabilization of approximately −20 kcal/mol.

The Effect of Enzymatic Depolymerization of Arterial Mucopolysaccharides on Sodium Ion Content and Vessel Reactivity

1971 ◽  
Vol 40 (4) ◽  
pp. 293-303 ◽  
Author(s):  
G. S. Harris ◽  
W. A. Palmer
Keyword(s):  
Cation Binding ◽  
Sodium Ion ◽  
Sodium Ions ◽  
High Concentration ◽  
Ion Content ◽  
Binding Properties ◽  
Arterial Walls ◽  
Testicular Hyaluronidase ◽  
Enzymatic Depolymerization

1. The presence of mucopolysaccharides within arterial walls may be associated with the high concentration of sodium ions within this tissue. These polyanions are sensitive to enzymatic depolymerization which results in a loss of the cation binding properties of the molecule. 2. In this study testicular hyaluronidase perfused through isolated arterial segments resulted in a decrease in reactivity of the artery to 65% that of control arteries. Associated with this finding was a 33% decrease in the sodium ion content of the stimulated hyaluronidase-treated artery. When a variety of other sympathetically innervated tissues were treated with hyaluronidase there was no decrease in reactivity or sodium ion content.

scholarly journals Exploration of inositol 1,4,5-trisphosphate (IP3) regulated dynamics of N-terminal domain of IP3 receptor reveals early phase molecular events during receptor activation

2018 ◽  
Author(s):  
Aneesh Chandran ◽  
Xavier Chee ◽  
David L. Prole ◽  
Taufiq Rahman
Keyword(s):  
Conformational Dynamics ◽  
Md Simulations ◽  
Receptor Activation ◽  
Activation Mechanism ◽  
Ip3 Receptor ◽  
Dynamic Correlation ◽  
Molecular Events ◽  
Binding Core ◽  
Domain Dynamics ◽  
Phosphate Groups

Inositol 1, 4, 5-trisphosphate (IP3) binding at the N-terminus (NT) of IP3 receptor (IP3R) allosterically triggers the opening of a Ca2+-conducting pore located ~ 100 Å away from the IP3-binding core (IBC). However, the precise mechanism of IP3 binding and correlated domain dynamics in the NT that are central to the IP3R activation, remains unknown. Our all-atom molecular dynamics (MD) simulations recapitulate the characteristic twist motion of the suppresser domain (SD) and reveal correlated ‘clam closure’ dynamics of IBC with IP3-binding, complementing existing suggestions on IP3R activation mechanism. Our study further reveals the existence of inter-domain dynamic correlation in the NT and establishes the SD to be critical for the conformational dynamics of IBC. Also, a tripartite interaction involving Glu283-Arg54-Asp444 at the SD – IBC interface seemed critical for IP3R activation. Intriguingly, during the sub-microsecond long simulation, we observed Arg269 undergoing an SD-dependent flipping of hydrogen bonding between the first and fifth phosphate groups of IP3. This seems to play a major role in determining the IP3 binding affinity of IBC in the presence/absence of the SD. Our study thus provides atomistic details of early molecular events occurring within the NT during and following IP3 binding that lead to channel gating.

scholarly journals Transport of Alzheimer’s associated amyloid-β catalyzed by P-glycoprotein

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0250371
Author(s):  
James W. McCormick ◽  
Lauren Ammerman ◽  
Gang Chen ◽  
Pia D. Vogel ◽  
John G. Wise
Keyword(s):  
Cell Culture ◽  
Atp Hydrolysis ◽  
Amyloid Β ◽  
Md Simulations ◽  
Membrane Transporter ◽  
Biochemical Activity ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Hydrolysis Activity

P-glycoprotein (P-gp) is a critical membrane transporter in the blood brain barrier (BBB) and is implicated in Alzheimer’s disease (AD). However, previous studies on the ability of P-gp to directly transport the Alzheimer’s associated amyloid-β (Aβ) protein have produced contradictory results. Here we use molecular dynamics (MD) simulations, transport substrate accumulation studies in cell culture, and biochemical activity assays to show that P-gp actively transports Aβ. We observed transport of Aβ40 and Aβ42 monomers by P-gp in explicit MD simulations of a putative catalytic cycle. In in vitro assays with P-gp overexpressing cells, we observed enhanced accumulation of fluorescently labeled Aβ42 in the presence of Tariquidar, a potent P-gp inhibitor. We also showed that Aβ42 stimulated the ATP hydrolysis activity of isolated P-gp in nanodiscs. Our findings expand the substrate profile of P-gp, and suggest that P-gp may contribute to the onset and progression of AD.

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