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1.
Anirban Basu Gopinatha Suresh Kumar 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(9):1995-2016
Background
Nucleic acids are now important targets for therapeutic intervention. Alkaloids are an important class of molecules that have myriad therapeutic utility. Isoquinoline and benzophenanthridine alkaloids exhibit multiple pharmacological activities which are often related to their strong nucleic acid binding abilities. Therefore, a review of their interaction aspects with varying nucleic acid structures is essential for rational design and development as therapeutic agents.Scope of the review
This work reviews the interaction of various therapeutically important isoquinoline and benzophenanthridine alkaloids with nucleic acids. The review lends insights into the molecular aspects of the interaction that is critical from the perspective of designing better therapeutics.Major conclusions
This review provides a concise report on the recent developments and advancements on the interaction of various alkaloids with natural and synthetic nucleic acids. The review focuses on the mode, mechanism, specificity, conformational aspects and energetics of the interaction that will be helpful in the design and synthesis nucleic acid targeted alkaloid analogs.General significance
The molecular aspects of the interaction presented here will benefit the development of effective drugs for many diseases. The fundamental results discussed in this review can serve as a database for the design and development of futuristic nucleic acid based small molecule therapeutics. 相似文献2.
Sophie Winkler Rupert Derler Bernd Gesslbauer Elmar Krieger Andreas J. Kungl 《Biochimica et Biophysica Acta (BBA)/General Subjects》2019,1863(3):528-533
Background
Binding of chemokines to glycosaminoglycans (GAGs) is a crucial step in leukocyte recruitment to inflamed tissues.Methods
A disaccharide compositional analysis of the HS dp6 fraction in combination with MS analysis of the CCL2-depleted dp6 fraction was the basis for target GAG ligand structure suggestions. Four experimentally-derived heparan sulfate hexasaccharides, two potentially chemokine-specific and two unspecific, have been docked to CCL2. Subsequent 300?ns molecular dynamics simulations were used to improve the docked complexes.Results
Hexasaccharides with four sulfations and no acetylations are suggested for selective and high affinity chemokine binding. Using the Antithromin-III/heparin complex as positive control for docking, we were able to recover the correct complex structure only if the previously liganded ATIII structure was used as input. Since the liganded structure is not known for a CCL2-GAG complex, we investigated if molecular dynamics simulations could improve initial docking results. We found that all four GAG oligosaccharides ended up in close contact with the known binding residues after about 100?ns simulation time.Conclusions
A discrimination of specific vs. unspecific CCL2 GAG ligands is not possible by this approach. Long-time molecular dynamics simulations are, however, well suited to capture the delicate enthalpy/entropy balance of GAG binding and improve results obtained from docking.General significance
With the comparison of two methods, MS-based ligand identification and molecular modelling, we have shown the current limitations of our molecular understanding of complex ligand binding which is could be due to the numerical inaccessibility of ligand-induced protein conformational changes. 相似文献3.
4.
Huan He Juan Xu Wen Xie Qing-Lian Guo Feng-Lei Jiang Yi Liu 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(3):501-512
Background
CDK6 is considered as a highly validated anticancer drug target due to its essential role in regulating cell cycle progression at G1 restriction point. Activation of CDK6 requires the phosphorylation of Thr177 on A-loop, but the structural insights of the activation mechanism remain unclear.Methods
Herein, all-atoms molecular dynamics (MD) simulations were used to study the effects of Thr177 phosphorylation on the dynamic structure of CDK6-Vcyclin complex.Results
MD results indicated that the free energy barrier of the transition from open to closed state decreased ~ 47.2% after Thr177 phosphorylation. Key steps along the state transition process were obtained from a cluster analysis. Binding preference of ten different inhibitors to open or closed state were also investigated through molecular docking along with MD simulations methods.Conclusions
Our results indicated that Thr177 phosphorylation increased the flexibility around the ATP-binding pocket. The transition of the ATP-binding pocket between open and closed states should be considered for understanding the binding of CDK6 inhibitors.General significance
This work could deepen the understanding of CDKs activation mechanism, and provide useful information for the discovery of new CDKs inhibitors with high affinity and specificity. 相似文献5.
Shreyasi Asthana Zaved Hazarika Parth Sarathi Nayak Jyoti Roy Anupam Nath Jha Bibekanand Mallick Suman Jha 《Biochimica et Biophysica Acta (BBA)/General Subjects》2019,1863(1):153-166
Background
Injection localized amyloidosis is one of the most prevalent disorders in type II diabetes mellitus (TIIDM) patients relying on insulin injections. Previous studies have reported that nanoparticles can play a role in the amyloidogenic process of proteins. Hence, the present study deals with the effect of zinc oxide nanoparticles (ZnONP) on the amyloidogenicity and cytotoxicity of insulin.Methods
ZnONP is synthesised and characterized using XRD, Zeta Sizer, UV-Visible spectroscope and TEM. The characterization is followed by ZnONP interaction with insulin, which is studied employing fluorescence spectroscopes, isothermal titration calorimetry and molecular dynamics simulations. The interaction leads insulin conformational rearrangement into amyloid-like fibril, which is studied using thioflavin T dye binding assay, circular dichroism spectroscopy and TEM, followed by cytotoxicity propensity using Alamar Blue dye reduction assay.Results
Insulin has very weak interaction with ZnONP interface. Insulin at studied concentration forms amorphous aggregates at physiological pH, whereas in presence of ZnONP interface amyloid-like fibrils are formed. While the amyloid-like fibrils are cytotoxic to MIN6 and THP-1 cell lines, insulin and ZnONP individual solutions and their fresh mixtures enhance the cells proliferation.Conclusions
The presence of ZnONP interface enhances insulin fibrillation at physiological pH by providing a favourable template for the nucleation and growth of insulin amyloids.General significance
The studied protein-nanoparticle system from protein conformational dynamics point of view throws caution over nanoparticle use in biological applications, especially in vivo applications, considering the amyloidosis a very slow but non-curable degenerative disease. 相似文献6.
Zhongjie Liang Junchi Hu Wenying Yan Hualiang Jiang Guang Hu Cheng Luo 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(7):1667-1679
Background
DNMT3A, as de novo DNA methyltransferase, is essential for regulating gene expression through cellular development and differentiation. The functions of DNMT3A rely on its oligomeric states and allosteric regulations between its catalytic domain and binding partners. Despite recent resolution of autoinhibitory and active DNMT3A/3L crystal structures, the mechanism of their functional motions and interdomain allostery in regulating the activity remains to be established.Methods
The hybrid approach, comprising Elastic Network Models coupled with information theory, Protein Structure Network, and sequence evolution analysis was employed to investigate intrinsic dynamics and allosteric properties of DNMT3A resolved in autoinhibitory and active states.Results
The conformational transition between two states is characterized by global motions, and the homo-dimer displays the similar dynamic properties as tetramer, acting as the basic functional unit. The hinge residues with restricted fluctuations are clustered at the dimer interface, which are predicted to enjoy remarkably efficient signal transduction properties. The allosteric pathways through the dimer interface are achieved by a cascade of interactions predominantly involving conserved and co-evolved residues.Conclusions
Our results suggest that structural topology coupled with global motions indicates the structural origin of the functional transformation of DNMT3A. The comprehensive analysis further highlights the pivotal role of the dimer interface of DNMT3A both in defining the quaternary structure dynamics and establishing interdomain communications.General significance
Understanding the global motions of DNMT3As not only provides mechanical insights into the functions of such molecular machines, but also reveals the mediators that determine their allosteric regulations. 相似文献7.
Michele Vitali Valentina Rigamonti Antonino Natalello Barbara Colzani Svetlana Avvakumova Stefania Brocca Carlo Santambrogio Joanna Narkiewicz Giuseppe Legname Miriam Colombo Davide Prosperi Rita Grandori 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(7):1556-1564
Background
Protein-nanoparticle (NP) interactions dictate properties of nanoconjugates relevant to bionanotechnology. Non-covalent adsorption generates a protein corona (PC) formed by an inner and an outer layer, the hard and soft corona (HC, SC). Intrinsically disordered proteins (IDPs) exist in solution as conformational ensembles, whose response to the presence of NPs is not known.Methods
Three IDPs (α-casein, Sic1 and α-synuclein) and lysozyme are compared, describing conformational properties inside HC on silica NPs by circular dichroism (CD) and Fourier-transform infrared (FTIR) spectroscopy.Results
IDPs inside HC are largely unstructured, but display small, protein-specific conformational changes. A minor increase in helical content is observed for α-casein and α-synuclein, reminiscent of membrane effects on α-synuclein. Frozen in their largely disordered conformation, bound proteins do not undergo folding induced by dehydration, as they do in their free forms. While HC thickness approaches the hydrodynamic diameter of the protein in solution for lysozyme, it is much below the respective values for IDPs. NPs boost α-synuclein aggregation kinetics in a dose-dependent manner.Conclusions
IDPs maintain structural disorder inside HC, experiencing minor, protein-specific, induced folding and stabilization against further conformational transitions, such as formation of intermolecular beta-sheets upon dehydration. The HC is formed by a single layer of protein molecules. SC likely plays a key role stabilizing amyloidogenic α-synuclein conformers.General significance
Protein-NP interactions can mimic those with macromolecular partners, allowing dissection of contributing factors by rational design of NP surfaces. Application of NPs in vivo should be carefully tested for amyloidogenic potential. 相似文献8.
Ryota Iino Tatsuya Iida Akihiko Nakamura Ei-ichiro Saita Huijuan You Yasushi Sako 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(2):241-252
Background
Biological molecular machines support various activities and behaviors of cells, such as energy production, signal transduction, growth, differentiation, and migration.Scope of review
We provide an overview of single-molecule imaging methods involving both small and large probes used to monitor the dynamic motions of molecular machines in vitro (purified proteins) and in living cells, and single-molecule manipulation methods used to measure the forces, mechanical properties and responses of biomolecules. We also introduce several examples of single-molecule analysis, focusing primarily on motor proteins and signal transduction systems.Major conclusions
Single-molecule analysis is a powerful approach to unveil the operational mechanisms both of individual molecular machines and of systems consisting of many molecular machines.General significance
Quantitative, high-resolution single-molecule analyses of biomolecular systems at the various hierarchies of life will help to answer our fundamental question: “What is life?” This article is part of a Special Issue entitled "Biophysical Exploration of Dynamical Ordering of Biomolecular Systems" edited by Dr. Koichi Kato. 相似文献9.
10.
Jun Wu Nana Tao Yao Tian Guanglin Xing Huihui Lv Junhai Han Chengqi Lin Wei Xie 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(3):440-450
Background
The functions of autism-associated Neuroligins (Nlgs) are modulated by their post-translational modifications, such as proteolytic cleavage. A previous study has shown that there are different endogenous forms of DNlg3 in Drosophila, indicating it may undergo proteolytic processing. However, the molecular mechanism underlying DNlg3 proteolytic processing is unknown. Here, we report a novel proteolytic mechanism that is essential for DNlg3 maturation and function in the nervous system.Methods
Molecular cloning, cell culture, immunohistochemistry, western blotting and genetic studies were employed to map the DNlg3 cleavage region, identify the protease and characterize the cleavage manner. Behavior analysis, immunohistochemistry and genetic manipulations were employed to study the functions of different DNlg3 forms in the nervous system and neuromuscular junction (NMJs).Results
Tumor necrosis factor α-converting enzyme (TACE) cleaved DNlg3 exclusively at its extracellular acetylcholinesterase-like domain to generate the N-terminal fragment and the short membrane-anchored fragment (sDNlg3). DNlg3 was constitutively processed in an activity-independent manner. Interestingly, DNlg3 was cleaved intracellularly in the Golgi apparatus before it arrived at the cell surface, a unique cleavage mechanism that is distinct from ‘conventional’ ectodomain shedding of membrane proteins, including rodent Nlg1. Genetic studies showed that sDNlg3 was essential for maintaining proper locomotor activity in Drosophila.Conclusions
Our results revealed a unique cleavage mechanism of DNlg3 and a neuron-specific role for DNlg3 maturation which is important in locomotor activity.General significance
Our study provides a new insight into a cleavage mechanism of Nlgs maturation in the nervous system. 相似文献11.
Dunja Urbančič Anita Kotar Alenka Šmid Marko Jukič Stanislav Gobec Lars-Göran Mårtensson Janez Plavec Irena Mlinarič-Raščan 《Biochimica et Biophysica Acta (BBA)/General Subjects》2019,1863(1):182-190
Background
Methylation driven by thiopurine S-methylatransferase (TPMT) is crucial for deactivation of cytostatic and immunosuppressant thiopurines. Despite its remarkable integration into clinical practice, the endogenous function of TPMT is unknown.Methods
To address the role of TPMT in methylation of selenium compounds, we established the research on saturation transfer difference (STD) and 77Se NMR spectroscopy, fluorescence measurements, as well as computational molecular docking simulations.Results
Using STD NMR spectroscopy and fluorescence measurements of tryptophan residues in TPMT, we determined the binding of selenocysteine (Sec) to human recombinant TPMT. By comparing binding characteristics of Sec in the absence and in the presence of methyl donor, we confirmed S-adenosylmethionine (SAM)-induced conformational changes in TPMT. Molecular docking analysis positioned Sec into the active site of TPMT with orientation relevant for methylation reaction. Se-methylselenocysteine (MeSec), produced in the enzymatic reaction, was detected by 77Se NMR spectroscopy. A direct interaction between Sec and SAM in the active site of rTPMT and the formation of both products, MeSec and S-adenosylhomocysteine, was demonstrated using NMR spectroscopy.Conclusions
The present study provides evidence on in vitro methylation of Sec by rTPMT in a SAM-dependant manner.General significance
Our results suggest novel role of TPMT and demonstrate new insights into enzymatic modifications of the 21st amino acid. 相似文献12.
Aminul Islam Khan Qian Lu Dan Du Yuehe Lin Prashanta Dutta 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(12):2779-2787
Background
Polymeric nanoparticles (PNP) have received significant amount of interests for targeted drug delivery across the blood-brain barrier (BBB). Experimental studies have revealed that PNP can transport drug molecules from microvascular blood vessels to brain parenchyma in an efficient and non-invasive way. Despite that, very little attention has been paid to theoretically quantify the transport of such nanoparticles across BBB.Methods
In this study, for the first time, we developed a mathematical model for PNP transport through BBB endothelial cells. The mathematical model is developed based on mass-action laws, where kinetic rate parameters are determined by an artificial neural network (ANN) model using experimental data from in-vitro BBB experiments.Results
The presented ANN model provides a much simpler way to solve the parameter estimation problem by avoiding integration scheme for ordinary differential equations associated with the mass-action laws. Furthermore, this method can efficiently deal with both small and large data set and can approximate highly nonlinear functions. Our results show that the mass-action model, constructed with ANN based rate parameters, can successfully predict the characteristics of the polymeric nanoparticle transport across the BBB.Conclusions
Our model results indicate that exocytosis of nanoparticles is seven fold slower to endocytosis suggesting that future studies should focus on enhancing the exocytosis process.General significance
This mathematical study will assist in designing new drug carriers to overcome the drug delivery problems in brain. Furthermore, we anticipate that this model will form the basis of future comprehensive models for drug transport across BBB. 相似文献13.
Christian Borgo Jordi Vilardell Valentina Bosello-Travain Lorenzo A. Pinna Andrea Venerando Mauro Salvi 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(12):2902-2910
Background
HSP27 plays a role in various diseases, including neurodegenerative diseases, ischemia, and atherosclerosis. It is particularly important in the regulation of the development, progression and metastasis of cancer as well as cell apoptosis and drug resistance. However, the absence of an ATP binding domain, that is, instead, present in other HSPs such as HSP90 and HSP70, hampers the development of small molecules as inhibitors of HSP27.Methods
Knockout cell lines generated by Crispr/Cas9 gene editing tool, specific kinase inhibitors and siRNA transfections were exploited to demonstrate that the expression of HSP27 is dependent on the integrity/activity of protein kinase CK2 holoenzyme. The interaction between these proteins has been confirmed by co-immunoprecipitation, confocal immunofluorescence microscopy, and by density gradient separation of protein complexes. Finally, using a proliferation assay this study demonstrates the potential efficacy of a combinatory therapy of heath shock and CK2 inhibitors in cancer treatment.Results
Our data demonstrate that CK2 is able to regulate HSP27 turnover by affecting the expression of its ubiquitin ligase SMURF2 (Smad ubiquitination regulatory factor 2). Moreover, for the first time we show an increased sensitivity of CK2-inhibited tumour cells to hyperthermia treatment.Conclusion
Being HSP27 involved in several pathological conditions, including protein conformational diseases (i.e Cystic Fibrosis) and cancer, the need of drugs to modulate its activity is growing and CK2-targeting could represent a new strategy to reduce cellular HSP27 level.General significance
This study identifies CK2 as a molecular target to control HSP27 cellular expression. 相似文献14.
Giulia Tedeschi Edoardo Salladini Carlo Santambrogio Rita Grandori Sonia Longhi Stefania Brocca 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(10):2204-2214
Background
Recent theoretical and computational studies have shown that the charge content and, most importantly, the linear distribution of opposite charges are major determinants of conformational properties of intrinsically disordered proteins (IDPs). Charge segregation in a sequence can be measured through κ, which represents a normalized measure of charge asymmetry. A strong inverse correlation between κ and radius of gyration has been previously demonstrated for two independent sets of permutated IDP sequences.Methods
We used two well-characterized IDPs, namely measles virus NTAIL and Hendra virus PNT4, sharing a very similar fraction of charged residues and net charge per residue, but differing in proline (Pro) content. For each protein, we have rationally designed a low- and a high-κ variant endowed with the highest and the lowest κ values compatible with their natural amino acid composition. Then, the conformational properties of wild-type and κ-variants have been assessed by biochemical and biophysical techniques.Results
We confirmed a direct correlation between κ and protein compaction. The analysis of our original data along with those available from the literature suggests that Pro content may affects the responsiveness to charge clustering.Conclusions
Charge clustering promotes IDP compaction, but the extent of its effects depends on the sequence context. Proline residues seem to play a role contrasting compaction.General significance
These results contribute to the identification of sequence determinants of IDP conformational properties. They may also serve as an asset for rational design of non-natural IDPs with tunable degree of compactness. 相似文献15.
Víctor G. Almendro-Vedia Carolina García Rubén Ahijado-Guzmán Diego de la Fuente-Herreruela Mónica Muñoz-Úbeda Paolo Natale Montserrat H. Viñas Rodrigo Queiroz Albuquerque Andrés Guerrero-Martínez Francisco Monroy M. Pilar Lillo Iván López-Montero 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(12):2824-2834
Background
The fluorescent dye 10-N-nonyl acridine orange (NAO) is widely used as a mitochondrial marker. NAO was reported to have cytotoxic effects in cultured eukaryotic cells when incubated at high concentrations. Although the biochemical response of NAO-induced toxicity has been well identified, the underlying molecular mechanism has not yet been explored in detail.Methods
We use optical techniques, including fluorescence confocal microscopy and lifetime imaging microscopy (FLIM) both in model membranes built up as giant unilamellar vesicles (GUVs) and cultured cells. These experiments are complemented with computational studies to unravel the molecular mechanism that makes NAO cytotoxic.Results
We have obtained direct evidence that NAO promotes strong membrane adhesion of negatively charged vesicles. The attractive forces are derived from van der Waals interactions between anti-parallel H-dimers of NAO molecules from opposing bilayers. Semi-empirical calculations have confirmed the supramolecular scenario by which anti-parallel NAO molecules form a zipper of bonds at the contact region. The membrane remodeling effect of NAO, as well as the formation of H-dimers, was also confirmed in cultured fibroblasts, as shown by the ultrastructure alteration of the mitochondrial cristae.Conclusions
We conclude that membrane adhesion induced by NAO stacking accounts for the supramolecular basis of its cytotoxicity.General significance
Mitochondria are a potential target for cancer and gene therapies. The alteration of the mitochondrial structure by membrane remodeling agents able to form supramolecular assemblies via adhesion properties could be envisaged as a new therapeutic strategy. 相似文献16.
Francesco Giangreco Siegfried Höfinger Evangelos Bakalis Francesco Zerbetto 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(9):1956-1963
Background
High levels of blood cholesterol are conventionally linked to an increased risk of developing cardiovascular disease (Grundy, 1986). Here we examine the molecular mode of action of natural products with known cholesterol-lowering activity, such as for example the green tea ingredient epigallocatechin gallate and a short pentapeptide, Ile-Ile-Ala-Glu-Lys.Methods
Molecular Dynamics simulations are used to gain insight into the formation process of mixed micelles and, correspondingly, how active agents epigallocatechin gallate and Ile-Ile-Ala-Glu-Lys could possibly interfere with it.Results
Self-assembly of physiological micelles occurs on the order of 35–50?ns; most of the structural properties of mixed micelles are unaffected by epigallocatechin gallate or Ile-Ile-Ala-Glu-Lys which integrate into the micellar surface; the diffusive motion of constituting lipids palmitoyl-oleoyl-phosphatidylcholine and cholesterol is significantly down-regulated by both epigallocatechin gallate and Ile-Ile-Ala-Glu-Lys;Conclusions
The molecular mode of action of natural compounds epigallocatechin gallate and Ile-Ile-Ala-Glu-Lys is a significant down-regulation of the diffusive motion of micellar lipids.General significance
Natural compounds like the green tea ingredient epigallocatechin gallate and a short pentapeptide, Ile-Ile-Ala-Glu-Lys, lead to a significant down-regulation of the diffusive motion of micellar lipids thereby modulating cholesterol absorption into physiological micelles. 相似文献17.
Kyung-Hwa Jeon Han Vit Yu Youngjoo Kwon 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(5):1126-1133
Background
Doxorubicin is commonly using chemotherapeutic agents for breast cancer. However, doxorubicin has limitations in clinical use because of dose-dependent cardiotoxicity and drug resistance. Despite of previously reported studies about mechanisms of doxorubicin resistance including overexpression of P-gp and abnormal expression and mutation of topoisomerase IIα, resistance to this agent still abundantly occur and is regarded as a major obstacle to successful treatment.Methods
We have established doxorubicin resistant T47D cells. Intracellular calcium and ROS levels and calpain activity were measured using fluorometric experiments. Cell viability assay, cell cycle analysis, immunofluorescence and western blot analysis were performed to evaluate m-calpain specific truncation of topoisomerase IIα and molecular mechanism in doxorubicin resistant cells.Results
We observed that doxorubicin treatment increased intracellular calcium and ROS (Reactive Oxygen Species) in parental and doxorubicin resistant T47D cells. The increases in intracellular calcium and ROS were much greater in doxorubicin resistant T47D cells, which led to higher activity of calpains. Hyperactivated m-calpain, but not μ-calpain, specifically induced cleavage of topoisomerase IIα and accumulation of truncated topoisomerase IIα in the cytoplasm. The increase in cytoplasmic truncated topoisomerase IIα reduced the efficacy of doxorubicin. Doxorubicin resistant T47D cells, with hyperactivated m-calpain and truncated cytosolic topoisomerase IIα, obtained cross-resistance to other topoisomerase II-targeting drugs.Conclusion
Hyperactivated m-calpain induced cytoplasmic accumulation of truncated topoisomerase IIα in doxorubicin resistant T47D cells.General significance
These data provide a new mechanism of doxorubicin resistance and suggest a novel strategy for overcoming drug resistance in topoisomerase IIα-targeting therapy. 相似文献18.
Sumangala Shetty Paul R. Copeland 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(11):2506-2510
Background
Selenoprotein synthesis requires the reinterpretation of a UGA stop codon as one that encodes selenocysteine (Sec), a process that requires a set of dedicated translation factors. Among the mammalian selenoproteins, Selenoprotein P (SELENOP) is unique as it contains a selenocysteine-rich domain that requires multiple Sec incorporation events.Scope of review
In this review we elaborate on new data and current models that provide insight into how SELENOP is made.Major conclusions
SELENOP synthesis requires a specific set of factors and conditions.General significance
As the key protein required for proper selenium distribution, SELENOP stands out as a lynchpin selenoprotein that is essential for male fertility, proper neurologic function and selenium metabolism. 相似文献19.
Fábio F. Cardoso Rafael J. Borges Thiago R. Dreyer Guilherme H.M. Salvador Walter L.G. Cavalcante Maeli Dal Pai Márcia Gallacci Marcos R.M. Fontes 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(12):2728-2737
Background
Specific compounds found in vegetal species have been demonstrated to be efficient inhibitors of snake toxins, such as phospholipase A2-like (PLA2-like) proteins. These particular proteins, present in several species of vipers (Viperidae), induce a severe local myotoxic effect in prey and human victims, and this effect is often not efficiently neutralized by the regular serum therapy. PLA2-like proteins have been functionally and structurally studied since the early 1990s; however, a comprehensive molecular mechanism was proposed only recently.Methods
Myographic and histological techniques were used to evaluate the inhibitory effect of chicoric acid (CA) against BthTX-I myotoxin. Isothermal titration calorimetry assays were used to measure the affinity between the inhibitor and the toxin. X-ray crystallography was used to reveal details of this interaction.Results
CA prevented the blockade of indirectly evoked muscle contraction and inhibited muscle damage induced by BthTX-I. The inhibitor binds to the toxin with the highest affinity measured for a natural compound in calorimetric assays. The crystal structure and molecular dynamics simulations demonstrated that CA binds at the entrance of the hydrophobic channel of the toxin and binds to one of the clusters that participates in membrane disruption.Conclusions
CA prevents the myotoxic activity of the toxin, preventing its activation by simultaneous binding with two critical regions.General significance
CA is a potential myotoxic inhibitor to other PLA2-like proteins and a possible candidate to complement serum therapy. 相似文献20.
Seong-Cheol Park Il Ryong Kim Jin-Young Kim Yongjae Lee Eun-Ji Kim Ji Hyun Jung Young Jun Jung Mi-Kyeong Jang Jung Ro Lee 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(12):2545-2554