scholarly journals Combining 3D structure with glycan array data provides insight into the origin of glycan specificity

Glycobiology ◽  
2016 ◽  
Vol 26 (7) ◽  
pp. 772-783 ◽  
Author(s):  
Oliver C Grant ◽  
Matthew B Tessier ◽  
Lawrence Meche ◽  
Lara K Mahal ◽  
Bethany L Foley ◽  
...  
Keyword(s):  
3D Structure ◽  
Glycan Array ◽  
Array Data ◽  
Insight Into

scholarly journals Electrostatics of Tau Protein by Molecular Dynamics

Biomolecules ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 116 ◽  
Author(s):  
Tarsila Castro ◽  
Florentina-Daniela Munteanu ◽  
Artur Cavaco-Paulo
Keyword(s):  
Molecular Dynamics ◽  
3D Structure ◽  
Three Dimensional ◽  
Dynamics Simulation ◽  
Microtubule Assembly ◽  
Interaction Sites ◽  
Disordered Protein ◽  
Fluid Environment ◽  
Function Relationship ◽  
Insight Into

Tau is a microtubule-associated protein that promotes microtubule assembly and stability. This protein is implicated in several neurodegenerative diseases, including Alzheimer’s. To date, the three-dimensional (3D) structure of tau has not been fully solved, experimentally. Even the most recent information is sometimes controversial in regard to how this protein folds, interacts, and behaves. Predicting the tau structure and its profile sheds light on the knowledge about its properties and biological function, such as the binding to microtubules (MT) and, for instance, the effect on ionic conductivity. Our findings on the tau structure suggest a disordered protein, with discrete portions of well-defined secondary structure, mostly at the microtubule binding region. In addition, the first molecular dynamics simulation of full-length tau along with an MT section was performed, unveiling tau structure when associated with MT and interaction sites. Electrostatics and conductivity were also examined to understand how tau affects the ions in the intracellular fluid environment. Our results bring a new insight into tau and tubulin MT proteins, their characteristics, and the structure–function relationship.

scholarly journals The cryoelectron microscopy structure of the human CDK-activating kinase

2020 ◽  
Vol 117 (37) ◽  
pp. 22849-22857 ◽  
Author(s):  
Basil J. Greber ◽  
Juan M. Perez-Bertoldi ◽  
Kif Lim ◽  
Anthony T. Iavarone ◽  
Daniel B. Toso ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Rna Polymerase Ii ◽  
Transcription Initiation ◽  
Rational Design ◽  
Control Cell ◽  
3D Structure ◽  
Structural Basis ◽  
Pol Ii ◽  
Insight Into ◽  
Cdk Activating Kinase

The human CDK-activating kinase (CAK), a complex composed of cyclin-dependent kinase (CDK) 7, cyclin H, and MAT1, is a critical regulator of transcription initiation and the cell cycle. It acts by phosphorylating the C-terminal heptapeptide repeat domain of the RNA polymerase II (Pol II) subunit RPB1, which is an important regulatory event in transcription initiation by Pol II, and it phosphorylates the regulatory T-loop of CDKs that control cell cycle progression. Here, we have determined the three-dimensional (3D) structure of the catalytic module of human CAK, revealing the structural basis of its assembly and providing insight into CDK7 activation in this context. The unique third component of the complex, MAT1, substantially extends the interaction interface between CDK7 and cyclin H, explaining its role as a CAK assembly factor, and it forms interactions with the CDK7 T-loop, which may contribute to enhancing CAK activity. We have also determined the structure of the CAK in complex with the covalently bound inhibitor THZ1 in order to provide insight into the binding of inhibitors at the CDK7 active site and to aid in the rational design of therapeutic compounds.

scholarly journals An in silico structural insights into Plasmodium LytB protein and its inhibition

2014 ◽  
Vol 70 (a1) ◽  
pp. C1791-C1791
Author(s):  
Rajabrata Bhunya ◽  
Suman Nandy ◽  
Alpana Seal
Keyword(s):  
In Silico ◽  
3D Structure ◽  
Three Dimensional ◽  
Comparative Modeling ◽  
Binding Energies ◽  
E Coli ◽  
Dimethylallyl Diphosphate ◽  
In Silico Study ◽  
Structural Insights ◽  
Insight Into

In most of the pathogenic organisms including Plasmodium falciparum, isoprenoids are synthesized via MEP (MethylErythritol 4-Phosphate) pathway. LytB is the last enzyme of this pathway which catalyzes the conversion of (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate (HMBPP) into the two isoprenoid precursors: isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Since the MEP pathway is not used by humans, it represents an attractive target for the development of new antimalarial compounds or inhibitors. Here a systematic in-silico study has been conducted to get an insight into the structure of Plasmodium lytB as well as its affinities towards different inhibitors. We used comparative modeling technique to predict the three dimensional (3D) structure of Plasmodium LytB taking E. Coli LytB protein (PDB ID: 3KE8) as template and the model was subsequently refined through molecular dynamics (MD) simulation. A large ligand dataset containing diphospate group was subjected for virtual screening against the target using GOLD 5.2 program. Considering the mode of binding and affinities, 17 leads were selected on basis of binding energies in comparison to its substrate HMBPP (Gold.Chemscore.DG: -20.9734 kcal/mol). Among them, 5 were discarded because of their inhibitory activity towards other human enzymes. The rest 12 potential leads carry all the properties of any "drug like" molecule and the knowledge of Plasmodium LytB inhibitory mechanism which can provide valuable support for the antimalarial inhibitor design in future.

scholarly journals Cryo-EM structure of native human thyroglobulin

2021 ◽  
Author(s):  
Ricardo Adaixo ◽  
Eva M. Steiner ◽  
Ricardo D. Righetto ◽  
Alexander Schmidt ◽  
Henning Stahlberg ◽  
...  
Keyword(s):  
Secretory Pathway ◽  
3D Structure ◽  
Vital Role ◽  
Hormone Synthesis ◽  
Cryo Electron Microscopy ◽  
Glycosylation Sites ◽  
Regulation Of Metabolism ◽  
Fundamental Understanding ◽  
Insight Into

The thyroglobulin (Tg) protein is essential to thyroid hormone synthesis, playing a vital role in the regulation of metabolism, development and growth. Its structure is conserved among vertebrates. Tg is delivered through the secretory pathway of the thyroid follicular unit to the central colloid depository, where it is iodinated at specific tyrosine sites to form mono- or diiodotyrosine, which combine to produce triiodothyronine (T3) and thyroxine (T4), respectively. Synthesis of these hormones depends on the precise 3D structure of Tg, which has remained unknown despite decades of research. Here, we present the cryo-electron microscopy structure of human thyroglobulin (hTg) to a global resolution of 3.2 Å. The structure provides detailed information on the location of the hTg hormonogenic sites and reveals the position as well as the role of many of its glycosylation sites. Our results offer structural insight into thyroid hormonogenesis and provide a fundamental understanding of clinically relevant hTg mutations, which can improve treatment of thyroid diseases.

scholarly journals Combining mass spectrometry and glycan array data to explore invertebrate glycomes

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Iain Wilson ◽  
Barbara Eckmair ◽  
Alba Hykollari ◽  
Shi Yan ◽  
Jorick Vanbeselaere ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Glycan Array ◽  
Array Data

scholarly journals Cryo-EM structure of native human thyroglobulin

2021 ◽  
Author(s):  
Ricardo Adaixo ◽  
Eva Steiner ◽  
Ricardo Righetto ◽  
Alexander Schmidt ◽  
Henning Stahlberg ◽  
...  
Keyword(s):  
Secretory Pathway ◽  
3D Structure ◽  
Vital Role ◽  
Hormone Synthesis ◽  
Cryo Electron Microscopy ◽  
Glycosylation Sites ◽  
Regulation Of Metabolism ◽  
Fundamental Understanding ◽  
Insight Into

Abstract The thyroglobulin (Tg) protein is essential to thyroid hormone synthesis, playing a vital role in the regulation of metabolism, development and growth. Its structure is conserved among vertebrates. Tg is delivered through the secretory pathway of the thyroid follicular unit to the central colloid depository, where it is iodinated at specific tyrosine sites to form mono- or diiodotyrosine, which combine to produce triiodothyronine (T3) and thyroxine (T4), respectively. Synthesis of these hormones depends on the precise 3D structure of Tg, which has remained unknown despite decades of research. Here, we present the cryo-electron microscopy structure of human thyroglobulin (hTg) to a global resolution of 3.2 Å. The structure provides detailed information on the location of the hTg hormonogenic sites and reveals the position as well as the role of many of its glycosylation sites. Our results offer structural insight into thyroid hormonogenesis and provide a fundamental understanding of clinically relevant hTg mutations, which can improve treatment of thyroid diseases.

scholarly journals Determining Lectin Specificity from Glycan Array Data Using Motif Segregation and GlycoSearch Software

2013 ◽  
Vol 5 (2) ◽  
pp. 157-169 ◽  
Author(s):  
Doron Kletter ◽  
Zheng Cao ◽  
Marshall Bern ◽  
Brian Haab
Keyword(s):  
Glycan Array ◽  
Array Data ◽  
Lectin Specificity

scholarly journals Thyroid Peroxidase Activity is Inhibited by Phenolic Compounds—Impact of Interaction

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2766
Author(s):  
Ewa Habza-Kowalska ◽  
Agnieszka A. Kaczor ◽  
Justyna Żuk ◽  
Dariusz Matosiuk ◽  
Urszula Gawlik-Dziki
Keyword(s):  
Chlorogenic Acid ◽  
Rosmarinic Acid ◽  
Molecular Level ◽  
Combination Index ◽  
3D Structure ◽  
Thyroid Peroxidase ◽  
Ic50 Values ◽  
Insight Into ◽  
Rutin And Quercetin

The aim of this study was to estimate the mode of thyroid peroxidase (TPO) inhibition by polyphenols: Chlorogenic acid, rosmarinic acid, quercetin, and rutin. All the tested polyphenols inhibited TPO; the IC50 values ranged from 0.004 mM to 1.44 mM (for rosmarinic acid and rutin, respectively). All these pure phytochemical substances exhibited different modes of TPO inhibition. Rutin and rosmarinic acid showed competitive, quercetin—uncompetitive and chlorogenic acid—noncompetitive inhibition effect on TPO. Homology modeling was used to gain insight into the 3D structure of TPO and molecular docking was applied to study the interactions of the inhibitors with their target at the molecular level. Moreover, the type and strength of mutual interactions between the inhibitors (expressed as the combination index, CI) were analyzed. Slight synergism, antagonism, and moderate antagonism were found in the case of the combined addition of the pure polyphenols. Rutin and quercetin as well as rutin and rosmarinic acid acted additively (CI = 0.096 and 1.06, respectively), while rutin and chlorogenic acid demonstrated slight synergism (CI = 0.88) and rosmarinic acid with quercetin and rosmarinic acid with chlorogenic acid showed moderate antagonism (CI = 1.45 and 1.25, respectively). The mixture of chlorogenic acid and quercetin demonstrated antagonism (CI = 1.79). All the polyphenols showed in vitro antiradical ability against 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid), ABTS. The highest ability (expressed as IC50) was exhibited by rosmarinic acid (0.12 mM) and the lowest value was ascribed to quercetin (0.45 mM).

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