Human serum albumin (HSA) is a monomeric, globular, multi-carrier and the most abundant protein in the blood. HSA displays multiple ligand binding sites with extraordinary binding capacity for a wide ...range of ions and molecules. For decades, HSA's ability to bind to various ligands has led many scientists to study its physiological properties and protein structure; indeed, a better understanding of HSA-ligand interactions in human blood, at the atomic level, will likely foster the development of more potent, and overall more performant, diagnostic and therapeutic tools against serious human disorders such as diabetes, cardiovascular disorders, and cancer. Here, we present a concise overview of the current knowledge of HSA's structural characteristics, and its coordination chemistry with transition metal ions, within the scope and limitations of current techniques and biophysical methods to reach atomic resolution in solution and in blood serum. We also highlight the overwhelming need of a detailed atomistic understanding of HSA dynamic structures and interactions that are transient, weak, multi-site and multi-step, and allosterically affected by each other. Considering the fact that HSA is a current clinical tool for drug delivery systems and a potential contender as molecular cargo and nano-vehicle used in biophysical, clinical and industrial fields, we underline the emerging need for novel approaches to target the dynamic functional coordination chemistry of the human blood serum albumin in solution, at the atomic level.
Schematic representation of human serum albumin (HSA) binding and coordination chemistry: HSA displays extraordinary binding capacity for a wide range of organic molecules and ions. Here, we present an overview of the current knowledge of HSA's high-resolution structural coordination chemistry, within the scope and limitations of current biophysical techniques. Display omitted
•Human serum albumin (HSA) exhibits dynamic structure with distinct spatial conformations.•HSA bears multi-binding sites and ligands modulate dynamic structures of HSA.•HSA interacts with wide range of endogenous and exogenous ligands.•Fatty acids modulate HSA affinity towards essential metal ions.•Emerging evidence points to the importance of HSA functional dynamics.
Flavonoids are phytochemical compounds present in many plants, fruits, vegetables, and leaves, with potential applications in medicinal chemistry. Flavonoids possess a number of medicinal benefits, ...including anticancer, antioxidant, anti-inflammatory, and antiviral properties. They also have neuroprotective and cardio-protective effects. These biological activities depend upon the type of flavonoid, its (possible) mode of action, and its bioavailability. These cost-effective medicinal components have significant biological activities, and their effectiveness has been proved for a variety of diseases. The most recent work is focused on their isolation, synthesis of their analogs, and their effects on human health using a variety of techniques and animal models. Thousands of flavonoids have been successfully isolated, and this number increases steadily. We have therefore made an effort to summarize the isolated flavonoids with useful activities in order to gain a better understanding of their effects on human health.
Flavonoids are natural phytochemicals known for their antiviral activity. The flavonoids acts at different stages of viral infection, such as viral entrance, replication and translation of proteins. ...Viruses cause various diseases such as SARS, Hepatitis, AIDS, Flu, Herpes, etc. These, and many more viral diseases, are prevalent in the world, and some (i.e. SARS-CoV-2) are causing global chaos. Despite much struggle, effective treatments for these viral diseases are not available. The flavonoid class of phytochemicals has a vast number of medicinally active compounds, many of which are studied for their potential antiviral activity against different DNA and RNA viruses. Here, we reviewed many flavonoids that showed antiviral activities in different testing environments such as in vitro, in vivo (mice model) and in silico. Some flavonoids had stronger inhibitory activities, showed no toxicity & the cell proliferation at the tested doses are not affected. Some of the flavonoids used in the in vivo studies also protected the tested mice prophylactically from lethal doses of virus, and effectively prevented viral infection. The glycosides of some of the flavonoids increased the solubility of some flavonoids, and therefore showed increased antiviral activity as compared to the non-glycoside form of that flavonoid. These phytochemicals are active against different disease-causing viruses, and inhibited the viruses by targeting the viral infections at multiple stages. Some of the flavonoids showed more potent antiviral activity than the market available drugs used to treat viral infections.
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•Flavonoids are the phytochemicals with many medicinal properties.•Different studies showed their potency against various human viral infections.•Novel flavonoids are required for better absorption and bioavailibilty.•Clinical trials are necessary; to further explore their antiviral properties.
Grain weight is one of the major factors determining single plant yield production of rice and other cereal crops. Research has begun to reveal the regulatory mechanisms underlying grain weight as ...well as grain size, highlighting the importance of this research for plant molecular biology. The developmental trait of grain weight is affected by multiple molecular and genetic aspects that lead to dynamic changes in cell division, expansion and differentiation. Additionally, several important biological pathways contribute to grain weight, such as ubiquitination, phytohormones, G-proteins, photosynthesis, epigenetic modifications and microRNAs. Our review integrates early and more recent findings, and provides future perspectives for how a more complete understanding of grain weight can optimize strategies for improving yield production. It is surprising that the acquired wealth of knowledge has not revealed more insights into the underlying molecular mechanisms. To accelerating molecular breeding of rice and other cereals is becoming an emergent and critical task for agronomists. Lastly, we highlighted the importance of leveraging gene editing technologies as well as structural studies for future rice breeding applications.
Folding of the Tau Protein on Microtubules Kadavath, Harindranath; Jaremko, Mariusz; Jaremko, Łukasz ...
Angewandte Chemie (International ed.),
August 24, 2015, Letnik:
54, Številka:
35
Journal Article
Recenzirano
Microtubules are regulated by microtubule‐associated proteins. However, little is known about the structure of microtubule‐associated proteins in complex with microtubules. Herein we show that the ...microtubule‐associated protein Tau, which is intrinsically disordered in solution, locally folds into a stable structure upon binding to microtubules. While Tau is highly flexible in solution and adopts a β‐sheet structure in amyloid fibrils, in complex with microtubules the conserved hexapeptides at the beginning of the Tau repeats two and three convert into a hairpin conformation. Thus, binding to microtubules stabilizes a unique conformation in Tau.
Tau the line: NMR spectroscopy shows that the protein Tau, which is intrinsically disordered in solution, locally folds into a stable structure upon binding to microtubules. While Tau is highly flexible in solution and forms a β‐sheet structure in amyloid fibrils, the conserved hexapeptides at the beginning of the second and third repeats in Tau adopt a hairpin conformation when bound to microtubules. Thus, binding to microtubules stabilizes a unique conformation in Tau.
Over the past two decades, nuclear magnetic resonance (NMR) has emerged as one of the three principal analytical techniques used in metabolomics (the other two being gas chromatography coupled to ...mass spectrometry (GC-MS) and liquid chromatography coupled with single-stage mass spectrometry (LC-MS)). The relative ease of sample preparation, the ability to quantify metabolite levels, the high level of experimental reproducibility, and the inherently nondestructive nature of NMR spectroscopy have made it the preferred platform for long-term or large-scale clinical metabolomic studies. These advantages, however, are often outweighed by the fact that most other analytical techniques, including both LC-MS and GC-MS, are inherently more sensitive than NMR, with lower limits of detection typically being 10 to 100 times better. This review is intended to introduce readers to the field of NMR-based metabolomics and to highlight both the advantages and disadvantages of NMR spectroscopy for metabolomic studies. It will also explore some of the unique strengths of NMR-based metabolomics, particularly with regard to isotope selection/detection, mixture deconvolution via 2D spectroscopy, automation, and the ability to noninvasively analyze native tissue specimens. Finally, this review will highlight a number of emerging NMR techniques and technologies that are being used to strengthen its utility and overcome its inherent limitations in metabolomic applications.
Polycomb repressive complex 1 (PRC1) is an essential chromatin-modifying complex that monoubiquitinates histone H2A and is involved in maintaining the repressed chromatin state. Emerging evidence ...suggests PRC1 activity in various cancers, rationalizing the need for small-molecule inhibitors with well-defined mechanisms of action. Here, we describe the development of compounds that directly bind to RING1B-BMI1, the heterodimeric complex constituting the E3 ligase activity of PRC1. These compounds block the association of RING1B-BMI1 with chromatin and inhibit H2A ubiquitination. Structural studies demonstrate that these inhibitors bind to RING1B by inducing the formation of a hydrophobic pocket in the RING domain. Our PRC1 inhibitor, RB-3, decreases the global level of H2A ubiquitination and induces differentiation in leukemia cell lines and primary acute myeloid leukemia (AML) samples. In summary, we demonstrate that targeting the PRC1 RING domain with small molecules is feasible, and RB-3 represents a valuable chemical tool to study PRC1 biology.
Salinity is one of the most prevalent abiotic stresses which not only limits plant growth and yield, but also limits the quality of food products. This study was conducted on the surface ...functionalization of phosphorus-rich mineral apatite nanoparticles (ANPs), with thiourea as a source of nitrogen (TU-ANPs) and through a co-precipitation technique for inducing osmotic stress tolerance in
. The resulting thiourea-capped apatite nanostructure (TU-ANP) was characterized using complementary analytical techniques, such as EDX, SEM, XRD and IR spectroscopy. The pre-sowing of soaked seeds of
in 1.00 µg/mL, 5.00 µg/mL and 10 µg/mL of TU-ANPs yielded growth under 0 mM, 60 mM and 100 mM osmotic stress of NaCl. The results show that Ca and P salt acted as precursors for the synthesis of ANPs at an alkaline pH of 10-11. Thiourea as a source of nitrogen stabilized the ANPs' suspension medium, leading to the synthesis of TU-ANPs. XRD diffraction analysis validated the crystalline nature of TU-ANPs with lattice dimensions of 29 nm, calculated from FWHM using the Sherrer equation. SEM revealed spherical morphology with polydispersion in size distribution. EDS confirmed the presence of Ca and P at a characteristic KeV, whereas IR spectroscopy showed certain stretches of binding functional groups associated with TU-ANPs. Seed priming with TU-ANPs standardized germination indices (
50,
,
and
) which were significantly declined by NaCl-based osmotic stress. Maximum values for biochemical parameters, such as sugar (39.8 mg/g at 10 µg/mL), protein (139.8 mg/g at 10 µg/mL) and proline (74.1 mg/g at 10 µg/mL) were recorded at different applied doses of TU-ANP. Antioxidant biosystems in the form of EC 1.11.1.6 catalase (11.34 IU/g FW at 10 µg/mL), EC 1.11.1.11 APX (0.95 IU/G FW at 10 µg/mL), EC 1.15.1.1 SOD (1.42 IU/g FW at 5 µg/mL), EC 1.11.1.7 POD (0.43 IU/g FW at 5 µg/mL) were significantly restored under osmotic stress. Moreover, photosynthetic pigments, such as chlorophyll A (2.33 mg/g at 5 µg/mL), chlorophyll B (1.99 mg/g at 5 µg/mL) and carotenoids (2.52 mg/g at 10 µg/mL), were significantly amplified under osmotic stress via the application of TU-ANPs. Hence, the application of TU-ANPs restores the growth performance of plants subjected to induced osmotic stress.
The process of aggregation of proteins and peptides is dependent on the concentration of proteins, and the rate of aggregation can be altered by the presence of metal ions, but this dependence is not ...always a straightforward relationship. In general, aggregation does not occur under normal physiological conditions, yet it can be induced in the presence of certain metal ions. However, the extent of the influence of metal ion interactions on protein aggregation has not yet been fully comprehended. A consensus has thus been difficult to reach because the acceleration/inhibition of the aggregation of proteins in the presence of metal ions depends on several factors such as pH and the concentration of the aggregated proteins involved as well as metal concentration level of metal ions. Metal ions, like Cu
2+
, Zn
2+
, Pb
2+
etc.
may either accelerate or inhibit aggregation simply because the experimental conditions affect the behavior of biomolecules. It is clear that understanding the relationship between metal ion concentration and protein aggregation will prove useful for future scientific applications. This review focuses on the dependence of the aggregation of selected important biomolecules (peptides and proteins) on metal ion concentrations. We review proteins that are prone to aggregation, the result of which can cause serious neurodegenerative disorders. Furthering our understanding of the relationship between metal ion concentration and protein aggregation will prove useful for future scientific applications, such as finding therapies for neurodegenerative diseases.
The process of aggregation of proteins and peptides is dependent on the concentration of proteins, and the rate of aggregation can be altered by the presence of metal ions, but this dependence is not always a straightforward relationship.
Cholesterol is an important regulator of membrane protein function. However, the exact mechanisms involved in this process are still not fully understood. Here we study how the tertiary and ...quaternary structure of the mitochondrial translocator protein TSPO, which binds cholesterol with nanomolar affinity, is affected by this sterol. Residue-specific analysis of TSPO by solid-state NMR spectroscopy reveals a dynamic monomer-dimer equilibrium of TSPO in the membrane. Binding of cholesterol to TSPO's cholesterol-recognition motif leads to structural changes across the protein that shifts the dynamic equilibrium towards the translocator monomer. Consistent with an allosteric mechanism, a mutation within the oligomerization interface perturbs transmembrane regions located up to 35 Å away from the interface, reaching TSPO's cholesterol-binding motif. The lower structural stability of the intervening transmembrane regions provides a mechanistic basis for signal transmission. Our study thus reveals an allosteric signal pathway that connects membrane protein tertiary and quaternary structure with cholesterol binding.
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