Solution NMR and racemic crystallography provide insights into a novel structural class of cyclic plant peptides

Head-to-tail cyclic and disulfide-rich peptides are natural products with applications in drug design. Among these are the PawS-Derived Peptides (PDPs) produced in seeds of the daisy plant family. PDP-23 is a unique member of this class in that it is twice the typical size and adopts two β-hairpins separated by a hinge region. The β-hairpins - both stabilised by a single disulfide bond - fold together into a V-shaped tertiary structure creating a hydrophobic core. In water two PDP-23 molecules merge their hydrophobic cores to form a square prism quaternary structure. Here, we synthesised PDP-23 and its enantiomer comprising all D-amino acids, which allowed us to confirm these solution NMR structural data by racemic crystallography. Furthermore, we discovered the related PDP-24. NMR analysis showed that PDP-24 does not form a dimeric structure and it has poor water solubility, but in less polar solvents adopts near identical secondary and tertiary structure to PDP-23. The natural role of these peptides in plants remains enigmatic, as we did not observe any antimicrobial or insecticidal activity. However, the plasticity of these larger PDPs and their ability to change structure under different conditions makes them appealing peptide drug scaffolds.

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NMR Studies of the Inclusion Complexes Between Ezetimibe and Cyclodextrins

Revista de Chimie ◽

10.37358/rc.18.7.6427 ◽

2018 ◽

Vol 69 (7) ◽

pp. 1838-1841

Author(s):

Hajnal Kelemen ◽

Angella Csillag ◽

Bela Noszal ◽

Gabor Orgovan

Keyword(s):

Inclusion Complex ◽

Inclusion Complexes ◽

Water Solubility ◽

Solution Nmr ◽

Spectroscopic Techniques ◽

Nmr Studies ◽

The Poor ◽

Poor Water Solubility

Ezetimibe, the antihyperlipidemic drug of poor bioavailability was complexed with native and derivatized cyclodextrins.The complexes were characterized in terms stability, stoichiometry and structure using various 1D and 2D solution NMR spectroscopic techniques. The complexes were found to be of moderate stability (logK[3). The least stable inclusion complex is formed with b-cyclodextrin, while the ezetimibe-methylated-b--cyclodextrin has a 7-fold higher stability. The results can be useful to improve the poor water-solubility and the concomitant bioavailability of ezetimibe.

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Folding and Intrinsic Disorder of the Receptor Tyrosine Kinase KIT Insert Domain Seen by Conventional Molecular Dynamics Simulations

International Journal of Molecular Sciences ◽

10.3390/ijms22147375 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7375

Author(s):

Julie Ledoux ◽

Alain Trouvé ◽

Luba Tchertanov

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Tertiary Structure ◽

Average Distance ◽

Intrinsic Disorder ◽

Accessible Surface Area ◽

Solvent Accessible Surface Area ◽

Hydrophobic Core ◽

Direct Evaluation ◽

Dynamics Simulations

The kinase insert domain (KID) of RTK KIT is the key recruitment region for downstream signalling proteins. KID, studied by molecular dynamics simulations as a cleaved polypeptide and as a native domain fused to KIT, showed intrinsic disorder represented by a set of heterogeneous conformations. The accurate atomistic models showed that the helical fold of KID is mainly sequence dependent. However, the reduced fold of the native KID suggests that its folding is allosterically controlled by the kinase domain. The tertiary structure of KID represents a compact array of highly variable α- and 310-helices linked by flexible loops playing a principal role in the conformational diversity. The helically folded KID retains a collapsed globule-like shape due to non-covalent interactions associated in a ternary hydrophobic core. The free energy landscapes constructed from first principles—the size, the measure of the average distance between the conformations, the amount of helices and the solvent-accessible surface area—describe the KID disorder through a collection of minima (wells), providing a direct evaluation of conformational ensembles. We found that the cleaved KID simulated with restricted N- and C-ends better reproduces the native KID than the isolated polypeptide. We suggest that a cyclic, generic KID would be best suited for future studies of KID f post-transduction effects.

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Effects of High Hydrostatic Pressure on the Conformational Structure and Gel Properties of Myofibrillar Protein and Meat Quality: A Review

Foods ◽

10.3390/foods10081872 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1872

Author(s):

Huipeng Liu ◽

Yiyuan Xu ◽

Shuyu Zu ◽

Xuee Wu ◽

Aimin Shi ◽

...

Keyword(s):

Hydrostatic Pressure ◽

High Hydrostatic Pressure ◽

Tertiary Structure ◽

Quaternary Structure ◽

Meat Products ◽

Myofibrillar Protein ◽

Conformational Structure ◽

Gel Properties ◽

The Relationship

In meat processing, changes in the myofibrillar protein (MP) structure can affect the quality of meat products. High hydrostatic pressure (HHP) has been widely utilized to change the conformational structure (secondary, tertiary and quaternary structure) of MP so as to improve the quality of meat products. However, a systematic summary of the relationship between the conformational structure (secondary and tertiary structure) changes in MP, gel properties and product quality under HHP is lacking. Hence, this review provides a comprehensive summary of the changes in the conformational structure and gel properties of MP under HHP and discusses the mechanism based on previous studies and recent progress. The relationship between the spatial structure of MP and meat texture under HHP is also explored. Finally, we discuss considerations regarding ways to make HHP an effective strategy in future meat manufacturing.

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Functional CBS modules make IMPDHs octameric

Acta Crystallographica Section A Foundations and Advances ◽

10.1107/s2053273314087166 ◽

2014 ◽

Vol 70 (a1) ◽

pp. C1283-C1283

Author(s):

Gilles Labesse ◽

Thomas Alexandre ◽

Laurène Vaupré ◽

Isabelle Salard-Arnaud ◽

Joséphine Lai Kee Him ◽

...

Keyword(s):

Analytical Ultracentrifugation ◽

Quaternary Structure ◽

Catalytic Domain ◽

Structural Data ◽

Site Directed Mutagenesis ◽

X Ray Crystallography ◽

Binding Pockets ◽

Essential Enzyme ◽

Cbs Domains

Inosine-5'-monophosphate dehydrogenase (1, 2) (IMPDH) is a major target for antiviral, antiparasitic, antileukemic and immunosuppressive therapies. It is an ubiquitous and essential enzyme for the biosynthesis of guanosine nucleotides. Up to now, IMPDHs have been reported as tetrameric enzymes harbouring a catalytic domain and a tandem of cystathionine-ß-synthase (CBS) modules. The latter had no precise function assigned despite their nearly absolute conservation among IMPDHs and consistent indication of their importance in vivo. The aim of our study was to provide evidence for the role of the CBS modules on the quaternary structure and on the regulation of IMPDHs. A multidisciplinary approach involving enzymology, site-directed mutagenesis, analytical ultracentrifugation, X-ray crystallography, SAXS, cryo-electron microscopy and molecular modelling allowed us to demonstrate that the Pseudomonas aeruginosa IMPDH is functionally active as an octamer and allosterically regulated by MgATP via each CBS module. Revisiting deposited structural data, we found this newly discovered octameric organization conserved in other IMPDH structures. Meanwhile, we demonstrated that the human IMPDH1 formed two distinct octamers that can pile up into isolated fibres in the presence of MgATP while its pathogenic mutant D226N, localised into the CBS domains, appeared to form massively aggregating fibres. The dramatic impact of this mutation could explain the severe retinopathy adRP10. Our data (3) revealed for the first time that IMPDH has an octameric architecture modulated by MgATP binding to the CBS modules, inducing large structural rearrangements. Thus, the regulatory CBS modules in IMPDHs are functional and they can either modulate catalysis or/and macromolecular assembly. Targeting the conserved effector binding pockets identified within the CBS modules might be promising to develop antibacterial compounds or drugs to counter retinopathy onset.

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Prediction of Protein Structural Classes: Features Extraction to Classification Algorithm

Current Proteomics ◽

10.2174/1570164618666210218141148 ◽

2021 ◽

Vol 18 ◽

Author(s):

Xiaoqing Liu ◽

Zhenyu Yang ◽

Yaoxin Wang ◽

Qi Dai

Keyword(s):

Tertiary Structure ◽

Protein Sequencing ◽

Conformational Space ◽

Folding Rate ◽

Class Prediction ◽

Structural Class ◽

Protein Structural Class ◽

Dna Binding Sites ◽

Structural Classes ◽

Protein Structure Data

: The fast growing of protein sequencing and protein structure data has promoted the development of the protein structural class prediction. Several prediction methods have been proposed to study protein folding rate, DNA binding sites, as well as reducing the search of conformational space and realizing the prediction of tertiary structure. This paper introduces the current approaches of protein structural class prediction and emphasize their steps from information extraction to classification algorithms.

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Systemically Delivered Magnetic Hyperthermia for Prostate Cancer Treatment

Pharmaceutics ◽

10.3390/pharmaceutics12111020 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1020

Author(s):

Hassan A. Albarqi ◽

Ananiya A. Demessie ◽

Fahad Y. Sabei ◽

Abraham S. Moses ◽

Mikkel N. Hansen ◽

...

Keyword(s):

Prostate Cancer ◽

Animal Studies ◽

Water Solubility ◽

Polymeric Nanoparticles ◽

Magnetic Hyperthermia ◽

Hydrophobic Core ◽

Prostate Cancer Treatment ◽

Novel Therapy ◽

Heating Efficiency ◽

Poly Ethylene

Herein, we report a novel therapy for prostate cancer based on systemically delivered magnetic hyperthermia. Conventional magnetic hyperthermia is a form of thermal therapy where magnetic nanoparticles delivered to cancer sites via intratumoral administration produce heat in the presence of an alternating magnetic field (AMF). To employ this therapy for prostate cancer tumors that are challenging to inject intratumorally, we designed novel nanoclusters with enhanced heating efficiency that reach prostate cancer tumors after systemic administration and generate desirable intratumoral temperatures upon exposure to an AMF. Our nanoclusters are based on hydrophobic iron oxide nanoparticles doped with zinc and manganese. To overcome the challenges associated with the poor water solubility of the synthesized nanoparticles, the solvent evaporation approach was employed to encapsulate and cluster them within the hydrophobic core of PEG-PCL (methoxy poly(ethylene glycol)-b-poly(ε-caprolactone))-based polymeric nanoparticles. Animal studies demonstrated that, following intravenous injection into mice bearing prostate cancer grafts, the nanoclusters efficiently accumulated in cancer tumors within several hours and increased the intratumoral temperature above 42 °C upon exposure to an AMF. Finally, the systemically delivered magnetic hyperthermia significantly inhibited prostate cancer growth and did not exhibit any signs of toxicity.

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Structural Aspects of Phenylalanylation and Quality Control in Three Major Forms of Phenylalanyl-tRNA Synthetase

Journal of Amino Acids ◽

10.4061/2010/983503 ◽

2010 ◽

Vol 2010 ◽

pp. 1-7 ◽

Cited By ~ 5

Author(s):

Liron Klipcan ◽

Igal Finarov ◽

Nina Moor ◽

Mark G. Safro

Keyword(s):

Quaternary Structure ◽

Thermus Thermophilus ◽

Three Dimensional ◽

Structural Diversity ◽

Structural Data ◽

Trna Synthetase ◽

Transfer Rnas ◽

Trna Synthetases ◽

Editing Activity ◽

Structural Aspects

Aminoacyl-tRNA synthetases (aaRSs) are a canonical set of enzymes that specifically attach corresponding amino acids to their cognate transfer RNAs in the cytoplasm, mitochondria, and nucleus. The aaRSs display great differences in primary sequence, subunit size, and quaternary structure. Existence of three types of phenylalanyl-tRNA synthetase (PheRS)—bacterial (αβ)2, eukaryotic/archaeal cytosolic (αβ)2, and mitochondrial α—is a prominent example of structural diversity within the aaRSs family. Although archaeal/eukaryotic and bacterial PheRSs share common topology of the core domains and the B3/B4 interface, where editing activity of heterotetrameric PheRSs is localized, the detailed investigation of the three-dimensional structures from three kingdoms revealed significant variations in the local design of their synthetic and editing sites. Moreover, as might be expected from structural data eubacterial, Thermus thermophilus and human cytoplasmic PheRSs acquire different patterns of tRNAPhe anticodon recognition.

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Different Synergy in Amyloids and Biologically Active Forms of Proteins

International Journal of Molecular Sciences ◽

10.3390/ijms20184436 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4436 ◽

Cited By ~ 2

Author(s):

Piotr Fabian ◽

Katarzyna Stapor ◽

Mateusz Banach ◽

Magdalena Ptak-Kaczor ◽

Leszek Konieczny ◽

...

Keyword(s):

Amino Acids ◽

Comparative Analysis ◽

Protein Structure ◽

Tertiary Structure ◽

Protein Structures ◽

Water Environment ◽

Biologically Active ◽

Radius Of Curvature ◽

Hydrophobic Core ◽

Structural Form

Protein structure is the result of the high synergy of all amino acids present in the protein. This synergy is the result of an overall strategy for adapting a specific protein structure. It is a compromise between two trends: The optimization of non-binding interactions and the directing of the folding process by an external force field, whose source is the water environment. The geometric parameters of the structural form of the polypeptide chain in the form of a local radius of curvature that is dependent on the orientation of adjacent peptide bond planes (result of the respective Phi and Psi rotation) allow for a comparative analysis of protein structures. Certain levels of their geometry are the criteria for comparison. In particular, they can be used to assess the differences between the structural form of biologically active proteins and their amyloid forms. On the other hand, the application of the fuzzy oil drop model allows the assessment of the role of amino acids in the construction of tertiary structure through their participation in the construction of a hydrophobic core. The combination of these two models—the geometric structure of the backbone and the determining of the participation in the construction of the tertiary structure that is applied for the comparative analysis of biologically active and amyloid forms—is presented.

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Image-based effective feature generation for protein structural class and ligand binding prediction

PeerJ Computer Science ◽

10.7717/peerj-cs.253 ◽

2020 ◽

Vol 6 ◽

pp. e253

Author(s):

Nafees Sadique ◽

Al Amin Neaz Ahmed ◽

Md Tajul Islam ◽

Md. Nawshad Pervage ◽

Swakkhar Shatabda

Keyword(s):

Machine Learning ◽

Ligand Binding ◽

Tertiary Structure ◽

Learning Algorithms ◽

Three Dimensional ◽

Machine Learning Algorithms ◽

Binding Prediction ◽

Structural Class ◽

Protein Structural Class ◽

Atom Bond

Proteins are the building blocks of all cells in both human and all living creatures of the world. Most of the work in the living organism is performed by proteins. Proteins are polymers of amino acid monomers which are biomolecules or macromolecules. The tertiary structure of protein represents the three-dimensional shape of a protein. The functions, classification and binding sites are governed by the protein’s tertiary structure. If two protein structures are alike, then the two proteins can be of the same kind implying similar structural class and ligand binding properties. In this paper, we have used the protein tertiary structure to generate effective features for applications in structural similarity to detect structural class and ligand binding. Firstly, we have analyzed the effectiveness of a group of image-based features to predict the structural class of a protein. These features are derived from the image generated by the distance matrix of the tertiary structure of a given protein. They include local binary pattern (LBP) histogram, Gabor filtered LBP histogram, separate row multiplication matrix with uniform LBP histogram, neighbor block subtraction matrix with uniform LBP histogram and atom bond. Separate row multiplication matrix and neighbor block subtraction matrix filters, as well as atom bond, are our novels. The experiments were done on a standard benchmark dataset. We have demonstrated the effectiveness of these features over a large variety of supervised machine learning algorithms. Experiments suggest support vector machines is the best performing classifier on the selected dataset using the set of features. We believe the excellent performance of Hybrid LBP in terms of accuracy would motivate the researchers and practitioners to use it to identify protein structural class. To facilitate that, a classification model using Hybrid LBP is readily available for use at http://brl.uiu.ac.bd/PL/. Protein-ligand binding is accountable for managing the tasks of biological receptors that help to cure diseases and many more. Therefore, binding prediction between protein and ligand is important for understanding a protein’s activity or to accelerate docking computations in virtual screening-based drug design. Protein-ligand binding prediction requires three-dimensional tertiary structure of the target protein to be searched for ligand binding. In this paper, we have proposed a supervised learning algorithm for predicting protein-ligand binding, which is a similarity-based clustering approach using the same set of features. Our algorithm works better than the most popular and widely used machine learning algorithms.

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