scholarly journals Activity-specificity trade-off gives PI5P4Kβ a nucleotide preference to function as a GTP-sensing kinase

2020 ◽  
Author(s):  
Koh Takeuchi ◽  
Yoshiki Ikeda ◽  
Miki Senda ◽  
Ayaka Harada ◽  
Koji Okuwaki ◽  
...  
Keyword(s):  
Binding Mode ◽  
Functional Evolution ◽  
Trade Off ◽  
Physiological Conditions ◽  
Nucleotide Base ◽  
Recognition Motif ◽  
Gtp Binding ◽  
Dependent Activity ◽  
Phosphate Donor ◽  
Mutational Study

SummaryMost kinases function with ATP. However, contrary to the prevailing dogma, phosphatidylinositol 5-phosphate 4-kinase β (PI5P4Kβ) utilizes GTP as a primary phosphate donor with a unique binding mode for GTP. Although PI5P4Kβ is evolved from a primordial ATP-utilizing enzyme, PI4P5K, how PI5P4Kβ evolutionarily acquired the GTP preference to function as a cellular GTP sensor remains unclear. In this study, we show that the short nucleotide base-recognition motif, TRNVF, is responsible for the GTP binding of PI5P4Kβ, and also confers onto PI5P4Kβ an unexpected specificity that extends to inosine triphosphate (ITP) and xanthosine triphosphate (XTP). A mutational study with GTP analogues suggests that the extended specificity is an obligatory consequence to the acquisition of GTP-dependent activity. However, as the cellular concentrations of ITP and XTP are typically negligible, PI5P4Kβ can still function as a GTP sensor, suggesting that the cellular physiological conditions leave room for the functional evolution of PI5P4Kβ.

scholarly journals The interaction of clenbuterol hydrochloride with bovine hemoglobin using spectroscopic techniques and molecular modeling methods

2009 ◽  
Vol 23 (5-6) ◽  
pp. 271-279 ◽  
Author(s):  
Yun Wu ◽  
Hui Mao ◽  
Bo Zhao ◽  
Jian Shen
Keyword(s):  
Molecular Modeling ◽  
Protein Secondary Structure ◽  
Binding Mode ◽  
Bovine Hemoglobin ◽  
Spectroscopic Techniques ◽  
Electronic Interaction ◽  
Physiological Conditions ◽  
Modeling Methods ◽  
Clenbuterol Hydrochloride ◽  
Hoff Equation

The interaction of clenbuterol hydrochloride (CL) to bovine hemoglobin (BHb) under physiological conditions was investigated by using UV-vis absorption, fluorescence, circular dichroism (CD) and molecular modeling. The fluorescence intensity of BHb decreased regularly with the gradual increasing concentration of CL. It is observed that there was a prominent interaction between CL and BHb. The fluorescence data revealed that the fluorescence quenching is a static process, and the thermodynamic parameters were calculated according to the Van't Hoff equation. The alternations of protein secondary structure in the presence of CL were determined by the evidence of CD. Molecular modeling study that corroborate our experimental results revealed that the binding mode of CL–BHb complex could be attributed to the hydrophobic interaction and hydrogen bonding, but electronic interaction cannot be excluded.

scholarly journals Extending the Inhibition Profiles of Coumarin-Based Compounds Against Human Carbonic Anhydrases: Synthesis, Biological, and In Silico Evaluation

Molecules ◽  
2019 ◽  
Vol 24 (19) ◽  
pp. 3580 ◽  
Author(s):  
Kartsev ◽  
Geronikaki ◽  
Bua ◽  
Nocentini ◽  
Petrou ◽  
...  
Keyword(s):  
Active Site ◽  
Inhibitory Activity ◽  
Binding Mode ◽  
Carbonic Anhydrases ◽  
Reference Drug ◽  
Physiological Conditions ◽  
Computational Procedures ◽  
Living Organisms ◽  
Human Isoforms ◽  
Potent Inhibitory Activity

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO2 hydration in all living organisms and are actively involved in the regulation of a plethora of pathological and physiological conditions. A set of new coumarin/ dihydrocoumarin derivatives was here synthesized, characterized, and tested as human CA inhibitors. Their inhibitory activity was evaluated against the cytosolic human isoforms hCA I and II and the transmembrane hCA IX and hCA XII. Two compounds showed potent inhibitory activity against hCA IX, being more active or equipotent with the reference drug acetazolamide. Computational procedures were used to investigate the binding mode of this class of compounds within the active site of hCA IX and XII that are validated as anti-tumor targets.

scholarly journals The ‘natural’ hybrid haemoglobin from mule. Interrelationships with its parent haemoglobins from horse and donkey

1992 ◽  
Vol 282 (2) ◽  
pp. 595-599 ◽  
Author(s):  
S G Condò ◽  
M Coletta ◽  
R Cicchetti ◽  
G Argentin ◽  
P Guerrieri ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Binding Mode ◽  
Natural Hybrid ◽  
Binding Properties ◽  
Inositol Hexakisphosphate ◽  
Physiological Conditions ◽  
General Terms ◽  
O2 Binding

The equilibrium O2-binding properties of the hybrid haemoglobin (Hb) present in vivo in erythrocytes from mule and of its parent Hbs from horse and donkey were compared with special reference to the effect of heterotropic ligands such as Cl-, D-glycerate 2,3-bisphosphate (DPG) and inositol hexakisphosphate. All these Hbs display a decreased effect by polyphosphates, confirming that what has been observed for horse Hb [Giardina, Brix, Clementi, Scatena, Nicoletti, Cicchetti, Argentin & Condò (1990) Biochem. J. 266, 897-900] is common to other equine species, at least from a qualitative standpoint. However, different quantitative aspects can be detected, which can be accounted for by a different role for the two types of chain in characterizing the binding free energy for the various heterotropic effectors. In particular, it is shown that the binding mode of DPG and inositol hexakisphosphate displays different features since long-range effects can be observed clearly for inositol hexakisphosphate but not for DPG. In general terms, in spite of a different intrinsic O2 affinity, the modulation of functional properties by third ligands leads these Hbs to behave, under physiological conditions, similarly to human HbA. It might represent an interesting example of how different species with similar functional needs find different ways to produce a similar functional behaviour.

A Study of the Mechanism of Binding between Neratinib and MAD2L1 Based on Molecular Simulation and Multi-spectroscopy Methods

2020 ◽  
Vol 25 (40) ◽  
pp. 4287-4295 ◽  
Author(s):  
Guangya Zhou ◽  
Manman Zhao ◽  
Ruirui Liang ◽  
Jiayang Xie ◽  
Xinyi Chen ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Conformational Change ◽  
Binding Sites ◽  
Biological Function ◽  
Kinase Inhibitor ◽  
Three Dimensional ◽  
Binding Mode ◽  
Physiological Conditions ◽  
Medicinal Value ◽  
Potential Binding

Background: Nilatinib is an irreversible tyrosine kinase inhibitor, which is used in the treatment of some kinds of cancer. To study the interaction between Neratinib and MAD2L1, a potential tumor target, is of guiding significance for enriching the medicinal value of Neratinib. Method: The binding mechanism between Mitotic arrest deficient 2-like protein 1 (MAD2L1) and Neratinib under simulative physiological conditions was investigated by molecule simulation and multi-spectroscopy approaches. Results: Molecular docking showed the most possible binding mode of Neratinib-MAD2L1 and the potential binding sites and interaction forces of the interaction between MAD2L1 and Neratinib. Fluorescence spectroscopy experiments manifested that Neratinib could interact with MAD2L1 and form a complex by hydrogen bond and van der Waals interaction. These results were consistent with the conclusions obtained from molecular docking. In addition, according to Synchronous fluorescence and three-dimensional fluorescence results, Neratinib might lead to the conformational change of MAD2L1, which may affect the biological functions of MAD2L1. Conclusion: This study indicated that Neratinib could interact with MAD2L1 and lead to the conformational change of MAD2L1. These works provide helpful insights for the further study of biological function of MAD2L1 and novel pharmacological utility of Neratinib.

DNase I – DNA interaction alters DNA and protein conformations

2008 ◽  
Vol 86 (3) ◽  
pp. 244-250 ◽  
Author(s):  
C.N. N’soukpoé-Kossi ◽  
S. Diamantoglou ◽  
H.A. Tajmir-Riahi
Keyword(s):  
Binding Constant ◽  
Protein Secondary Structure ◽  
Binding Mode ◽  
Dna Interaction ◽  
Minor Groove ◽  
Dnase I ◽  
Protein Conformations ◽  
Physiological Conditions ◽  
Α Helix ◽  
The Right

Human DNase I is an endonuclease that catalyzes the hydrolysis of double-stranded DNA predominantly by a single-stranded nicking mechanism under physiological conditions in the presence of divalent Mg and Ca cations. It binds to the minor groove and the backbone phosphate group and has no contact with the major groove of the right-handed DNA duplex. The aim of this study was to examine the effects of DNase I – DNA complexation on DNA and protein conformations.We monitored the interaction of DNA with DNase I under physiological conditions in the absence of Mg2+, with a constant DNA concentration (12.5 mmol/L; phosphate) and various protein concentrations (10–250 µmol/L). We used Fourier transfrom infrared, UV-visible, and circular dichroism spectroscopic methods to determine the protein binding mode, binding constant, and effects of polynucleotide–enzyme interactions on both DNA and protein conformations. Structural analyses showed major DNase–PO2 binding and minor groove interaction, with an overall binding constant, K, of 5.7 × 105 ± 0.78 × 105 (mol/L)–1. We found that the DNase I – DNA interaction altered protein secondary structure, with a major reduction in α helix and an increase in β sheet and random structures, and that a partial B-to-A DNA conformational change occurred. No DNA digestion was observed upon protein–DNA complexation.

scholarly journals Models of knowledge and systems of governance

2005 ◽  
Vol 1 (1) ◽  
pp. 51-73 ◽  
Author(s):  
CRISTIANO ANTONELLI
Keyword(s):  
Public Policy ◽  
Public Good ◽  
Policy Making ◽  
Technological Knowledge ◽  
Governance Mechanisms ◽  
Public Policy Making ◽  
Trade Off ◽  
Dependent Activity ◽  
Path Dependent

The analysis of the main features of knowledge, in terms of domain, characteristics and processes makes it possible to trace significant shifts in the economics of knowledge. Changing emphasis about the role of knowledge appropriability, divisibility and tradability has provided different solutions to the knowledge trade-off. Three different and rival concepts of technological knowledge can be identified: (a) knowledge as a public good, (b) knowledge as a proprietary good, (c) knowledge as a localized, collective and complex, path dependent activity. Such a shift has relevant implications in terms of governance mechanisms, strategic attitude of agents and public policy making.

scholarly journals Chromene-Containing Aromatic Sulfonamides with Carbonic Anhydrase Inhibitory Properties

2021 ◽  
Vol 22 (10) ◽  
pp. 5082
Author(s):  
Andrea Angeli ◽  
Victor Kartsev ◽  
Anthi Petrou ◽  
Mariana Pinteala ◽  
Volodymyr Brovarets ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Active Site ◽  
Inhibitory Activity ◽  
Binding Mode ◽  
Carbonic Anhydrases ◽  
Inhibition Activity ◽  
Physiological Conditions ◽  
Computational Procedures ◽  
Living Organisms ◽  
Human Isoforms

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. Their inhibitory activity was assessed against the cytosolic human isoforms hCA I, hCA II and the transmembrane hCA IX and XII. Several of the investigated derivatives showed interesting inhibition activity towards the tumor associate isoforms hCA IX and hCA XII. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds, within the active site of hCA IX.

Ultrastructure of Giant Mitochondria and Their Inclusions in Schwann Cells of Bovine Splenic Nerve

1974 ◽  
Vol 32 ◽  
pp. 194-195
Author(s):  
Å. Thureson-Klein
Keyword(s):  
Schwann Cells ◽  
Cell Organelles ◽  
Giant Mitochondria ◽  
Matrix Density ◽  
Physiological Conditions ◽  
Unmyelinated Axons ◽  
Internal Structures ◽  
Structural Abnormalities ◽  
Cytotoxic Compounds ◽  
Cell Components

Giant mitochondria of various shapes and with different internal structures and matrix density have been observed in a great number of tissues including nerves. In most instances, the presence of giant mitochondria has been associated with a known disease or with abnormal physiological conditions such as anoxia or exposure to cytotoxic compounds. In these cases degenerative changes occurred in other cell organelles and, therefore the giant mitochondria also were believed to be induced structural abnormalities.Schwann cells ensheating unmyelinated axons of bovine splenic nerve regularly contain giant mitochondria in addition to the conventional smaller type (Fig. 1). These nerves come from healthy inspected animals presumed not to have been exposed to noxious agents. As there are no drastic changes in the small mitochondria and because other cell components also appear reasonably well preserved, it is believed that the giant mitochondria are normally present jin vivo and have not formed as a post-mortem artifact.

Freeze-fracture observations on changes in the distribution of Filipin-sterol complexes during epididymal maturation and capacitation of boar spermatozoa

1990 ◽  
Vol 48 (3) ◽  
pp. 90-91
Author(s):  
N. Seki ◽  
Y. Toyama ◽  
T. Nagano
Keyword(s):  
Plasma Membrane ◽  
Essential Role ◽  
Freeze Fracture ◽  
Final Concentration ◽  
Freeze Fracturing ◽  
Physiological Conditions ◽  
Epididymal Maturation ◽  
Cacodylate Buffer ◽  
Sperm Membrane ◽  
Boar Spermatozoa

It is believed that i ntramembra.nous sterols play an essential role in membrane stability and permeability. To investigate the distribution changes of sterols in sperm membrane during epididymal maturation and capacitation, filipin has been used as a cytochemical probe for the detection for membrane sterols. Using this technique in combination with freeze fracturing, we examined the boar spermatozoa under various physiological conditions.The spermatozoa were collected from: 1) caput, corpus and cauda epididymides, 2) sperm rich fraction of ejaculates, and 3)the uterus 2hr after natural coition. They were fixed with 2.5% glutaraldehyde in 0.05M cacodylate buffer (pH 7.4), and treated with the filipin solution (final concentration : 0.02.0.05%) for 24hr at 4°C with constant agitation. After the filipin treatment, replicas were made by conventional freeze-fracture technique. The density of filipin-sterol complexes (FSCs) was determined in the E face of the plasma membrane of head regions.

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