scholarly journals The Relevance of Structural Biology in Studying Molecules Involved in Parasite–Host Interactions: Potential for Designing New Interventions

2014 ◽  
Vol 67 (12) ◽  
pp. 1732 ◽  
Author(s):  
Lyndel Mason ◽  
Parisa Amani ◽  
Megan Cross ◽  
Joshua Baker ◽  
Ulla-Maja Bailey ◽  
...  
Keyword(s):  
Structural Biology ◽  
Molecular Level ◽  
Three Dimensional ◽  
Structural Features ◽  
Detailed Knowledge ◽  
Common Theme ◽  
Host Interactions ◽  
Genome Annotations ◽  
Structure Of Proteins ◽  
Biology Research

New interventions against infectious diseases require a detailed knowledge and understanding of pathogen–host interactions and pathogeneses at the molecular level. The combination of the considerable advances in systems biology research with methods to explore the structural biology of molecules is poised to provide new insights into these areas. Importantly, exploring three-dimensional structures of proteins is central to understanding disease processes, and establishing structure–function relationships assists in identification and assessment of new drug and vaccine targets. Frequently, the molecular arsenal deployed by invading pathogens, and in particular parasites, reveals a common theme whereby families of proteins with conserved three-dimensional folds play crucial roles in infectious processes, but individual members of such families show high levels of specialisation, which is often achieved through grafting particular structural features onto the shared overall fold. Accordingly, the applicability of predictive methodologies based on the primary structure of proteins or genome annotations is limited, particularly when thorough knowledge of molecular-level mechanisms is required. Such instances exemplify the need for experimental three-dimensional structures provided by protein crystallography, which remain an essential component of this area of research. In the present article, we review two examples of key protein families recently investigated in our laboratories, which could represent intervention targets in the metabolome or secretome of parasites.

Membrane protein crystallography in the era of modern structural biology

2020 ◽  
Vol 48 (6) ◽  
pp. 2505-2524
Author(s):  
Tristan O. C. Kwan ◽  
Danny Axford ◽  
Isabel Moraes
Keyword(s):  
Structural Biology ◽  
Molecular Level ◽  
Protein Structures ◽  
Three Dimensional ◽  
Biological Macromolecules ◽  
X Ray ◽  
X Ray Crystallography ◽  
Cellular Processes ◽  
Biochemical Level

The aim of structural biology has been always the study of biological macromolecules structures and their mechanistic behaviour at molecular level. To achieve its goal, multiple biophysical methods and approaches have become part of the structural biology toolbox. Considered as one of the pillars of structural biology, X-ray crystallography has been the most successful method for solving three-dimensional protein structures at atomic level to date. It is however limited by the success in obtaining well-ordered protein crystals that diffract at high resolution. This is especially true for challenging targets such as membrane proteins (MPs). Understanding structure-function relationships of MPs at the biochemical level is vital for medicine and drug discovery as they play critical roles in many cellular processes. Though difficult, structure determination of MPs by X-ray crystallography has significantly improved in the last two decades, mainly due to many relevant technological and methodological developments. Today, numerous MP crystal structures have been solved, revealing many of their mechanisms of action. Yet the field of structural biology has also been through significant technological breakthroughs in recent years, particularly in the fields of single particle electron microscopy (cryo-EM) and X-ray free electron lasers (XFELs). Here we summarise the most important advancements in the field of MP crystallography and the significance of these developments in the present era of modern structural biology.

scholarly journals Michael G. Rossmann (1930–2019), pioneer in macromolecular and virus crystallography: scientist, mentor and friend

2019 ◽  
Vol 75 (6) ◽  
pp. 523-527
Author(s):  
Eddy Arnold ◽  
Hao Wu ◽  
John E. Johnson
Keyword(s):  
World War Ii ◽  
Structural Biology ◽  
Molecular Level ◽  
Protein Structures ◽  
Three Dimensional ◽  
Biological Molecules ◽  
World War ◽  
Biological Structure ◽  
Vast Array ◽  
Health And Disease

Michael George Rossmann, who made monumental contributions to science, passed away peacefully in West Lafayette, Indiana on 14 May 2019 at the age of 88, following a courageous five-year battle with cancer. Michael was born in Frankfurt, Germany on 30 July 1930. As a young boy, he emigrated to England with his mother just as World War II ignited. Michael was a highly innovative and energetic person, well known for his intensity, persistence and focus in pursuing his research goals. Michael was a towering figure in crystallography as a highly distinguished faculty member at Purdue University for 55 years. Michael made many seminal contributions to crystallography in a career that spanned the entirety of structural biology, beginning in the 1950s at Cambridge where the first protein structures were determined in the laboratories of Max Perutz (hemoglobin, 1960) and John Kendrew (myoglobin, 1958). Michael's work was central in establishing and defining the field of structural biology, which amazingly has described the structures of a vast array of complex biological molecules and assemblies in atomic detail. Knowledge of three-dimensional biological structure has important biomedical significance including understanding the basis of health and disease at the molecular level, and facilitating the discovery of many drugs.

scholarly journals Stereoscopic Methods in TEM

1975 ◽  
Vol 33 ◽  
pp. 294-295
Author(s):  
L. E. Thomas
Keyword(s):  
Molecular Level ◽  
Microstructural Analysis ◽  
Three Dimensional ◽  
Structural Features ◽  
Cellular Level ◽  
Image Resolution ◽  
Three Dimensions ◽  
Reconstruction Methods ◽  
Human Ability ◽  
Point Defect Clusters

The use of stereoscopy to characterize three-dimensional structures observed by TEM has become widespread since the introduction of instruments operating at 1 MV. In its emphasis on whole structures and thick specimens this approach differs significantly from conventional methods of microstructural analysis based on three-dimensional image reconstruction from a number of thin-section views. The great advantage of stereo derives from the ability to directly perceive and measure structures in three-dimensions by capitalizing on the unsurpassed human ability for stereoscopic matching of corresponding details on picture pairs showing the same features from different viewpoints. At this time, stereo methods are aimed mainly at structural understanding at the level of dislocations, precipitates and irradiation-induced point-defect clusters in crystal and on the cellular level of biological specimens. 3-d reconstruction methods have concentrated on the molecular level where image resolution requirements dictate the use of very thin specimens.For the most part the stereo methods used in TEM are direct and unsophisticated. Stereo pairs of micrographs are taken by tilting the specimen to record two views of the same structural features from viewpoints ten or so degrees apart.

Methods for making stereoslides and -prints, with freeze-etched olfactory epithelium as example

1984 ◽  
Vol 42 ◽  
pp. 704-705
Author(s):  
Bert Ph. M. Menco ◽  
Ido F. Menco ◽  
Frans L.T. Verdonk
Keyword(s):  
Electron Microscope ◽  
Olfactory Epithelium ◽  
Three Dimensional ◽  
Supporting Cell ◽  
Structural Features ◽  
Extensive Study ◽  
Sprague Dawley ◽  
Freezing Method ◽  
Respiratory Epithelia ◽  
Three Dimensional Presentation

Previously we presented an extensive study of the distributions of intramembranous particles of structures in apical surfaces of nasal olfactory and respiratory epithelia of the Sprague-Dawley rat. For the same structures these distributions were compared in samples which were i) chemically fixed and cryo-protected with glycerol before cryo-fixation, after excision, and ii)ultra-rapidly frozen by means of the slam-freezing method. Since a three-dimensional presentation markedly improves visualization of structural features micrographs were presented as stereopairs. Two exposures were made by tiling the sample stage of the electron microscope 6° in either direction with an eucentric goniometer. The negatives (Agfa Pan 25 Professional) were reversed with Kodak Technical Pan Film 2415 developed in D76 1:1. The prints were made from these reversed negatives. As an example tight-junctional features of an olfactory supporting cell in a region where this cell conjoined with two other cells are presented (Fig. 1).

scholarly journals The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lucia Silvestrini ◽  
Norhan Belhaj ◽  
Lucia Comez ◽  
Yuri Gerelli ◽  
Antonino Lauria ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Dissociation Constant ◽  
Molecular Mechanisms ◽  
Antiviral Drug ◽  
Structural Features ◽  
Experimental Information ◽  
Detailed Knowledge ◽  
Main Protease ◽  
Equilibrium Dissociation ◽  
Drug Leads

AbstractThe maturation of coronavirus SARS-CoV-2, which is the etiological agent at the origin of the COVID-19 pandemic, requires a main protease Mpro to cleave the virus-encoded polyproteins. Despite a wealth of experimental information already available, there is wide disagreement about the Mpro monomer-dimer equilibrium dissociation constant. Since the functional unit of Mpro is a homodimer, the detailed knowledge of the thermodynamics of this equilibrium is a key piece of information for possible therapeutic intervention, with small molecules interfering with dimerization being potential broad-spectrum antiviral drug leads. In the present study, we exploit Small Angle X-ray Scattering (SAXS) to investigate the structural features of SARS-CoV-2 Mpro in solution as a function of protein concentration and temperature. A detailed thermodynamic picture of the monomer-dimer equilibrium is derived, together with the temperature-dependent value of the dissociation constant. SAXS is also used to study how the Mpro dissociation process is affected by small inhibitors selected by virtual screening. We find that these inhibitors affect dimerization and enzymatic activity to a different extent and sometimes in an opposite way, likely due to the different molecular mechanisms underlying the two processes. The Mpro residues that emerge as key to optimize both dissociation and enzymatic activity inhibition are discussed.

scholarly journals Agent-Based Modeling Demonstrates How Local Chemotactic Behavior Can Shape Biofilm Architecture

mSphere ◽  
2019 ◽  
Vol 4 (3) ◽  
Author(s):  
Emily G. Sweeney ◽  
Andrew Nishida ◽  
Alexandra Weston ◽  
Maria S. Bañuelos ◽  
Kristin Potter ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Three Dimensional ◽  
Structural Features ◽  
Agent Based Modeling ◽  
Emergent Properties ◽  
Cellular Interactions ◽  
Biofilm Growth ◽  
Content Type ◽  
Agent Based ◽  
H Pylori

ABSTRACTBacteria are often found living in aggregated multicellular communities known as biofilms. Biofilms are three-dimensional structures that confer distinct physical and biological properties to the collective of cells living within them. We used agent-based modeling to explore whether local cellular interactions were sufficient to give rise to global structural features of biofilms. Specifically, we asked whether chemorepulsion from a self-produced quorum-sensing molecule, autoinducer-2 (AI-2), was sufficient to recapitulate biofilm growth and cellular organization observed for biofilms ofHelicobacter pylori, a common bacterial resident of human stomachs. To carry out this modeling, we modified an existing platform, Individual-based Dynamics of Microbial Communities Simulator (iDynoMiCS), to incorporate three-dimensional chemotaxis, planktonic cells that could join or leave the biofilm structure, and cellular production of AI-2. We simulated biofilm growth of previously characterizedH. pyloristrains with various AI-2 production and sensing capacities. Using biologically plausible parameters, we were able to recapitulate both the variation in biofilm mass and cellular distributions observed with these strains. Specifically, the strains that were competent to chemotax away from AI-2 produced smaller and more heterogeneously spaced biofilms, whereas the AI-2 chemotaxis-defective strains produced larger and more homogeneously spaced biofilms. The model also provided new insights into the cellular demographics contributing to the biofilm patterning of each strain. Our analysis supports the idea that cellular interactions at small spatial and temporal scales are sufficient to give rise to larger-scale emergent properties of biofilms.IMPORTANCEMost bacteria exist in aggregated, three-dimensional structures called biofilms. Although biofilms play important ecological roles in natural and engineered settings, they can also pose societal problems, for example, when they grow in plumbing systems or on medical implants. Understanding the processes that promote the growth and disassembly of biofilms could lead to better strategies to manage these structures. We had previously shown thatHelicobacter pyloribacteria are repulsed by high concentrations of a self-produced molecule, AI-2, and thatH. pylorimutants deficient in AI-2 sensing form larger and more homogeneously spaced biofilms. Here, we used computer simulations of biofilm formation to show that localH. pyloribehavior of repulsion from high AI-2 could explain the overall architecture ofH. pyloribiofilms. Our findings demonstrate that it is possible to change global biofilm organization by manipulating local cell behaviors, which suggests that simple strategies targeting cells at local scales could be useful for controlling biofilms in industrial and medical settings.

scholarly journals Porous Characteristics of Three-Dimensional Disordered Graphene Networks

Crystals ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 127
Author(s):  
YongChao Wang ◽  
YinBo Zhu ◽  
HengAn Wu
Keyword(s):  
Pore Size ◽  
Low Temperatures ◽  
Gas Adsorption ◽  
Three Dimensional ◽  
Md Simulations ◽  
Structural Features ◽  
Atomic Scale ◽  
Critical Factors ◽  
Chlorination Process ◽  
Porous Morphology

The porous characteristics of disordered carbons are critical factors to their performance on hydrogen storage and electrochemical capacitors. Even though the porous information can be estimated indirectly by gas adsorption experiments, it is still hard to directly characterize the porous morphology considering the complex 3D connectivity. To this end, we construct full-atom disordered graphene networks (DGNs) by mimicking the chlorination process of carbide-derived carbons using annealing-MD simulations, which could model the structure of disordered carbons at the atomic scale. The porous characteristics, including pore volume, pore size distribution (PSD), and specific surface area (SSA), were then computed from the coordinates of carbon atoms. From the evolution of structural features, pores grow dramatically during the formation of polyaromatic fragments and sequent disordered framework. Then structure is further graphitized while the PSD shows little change. For the obtained DGNs, the porosity, pore size, and SSA increase with decreasing density. Furthermore, SSA tends to saturate in the low-density range. The DGNs annealed at low temperatures exhibit larger SSA than high-temperature DGNs because of the abundant free edges.

scholarly journals Three-Dimensional Structures of Carbohydrates and Where to Find Them

2020 ◽  
Vol 21 (20) ◽  
pp. 7702 ◽  
Author(s):  
Sofya I. Scherbinina ◽  
Philip V. Toukach
Keyword(s):  
Experimental Data ◽  
Molecular Modeling ◽  
Computational Methods ◽  
Three Dimensional ◽  
Structural Diversity ◽  
Structural Data ◽  
Structural Features ◽  
Data Validation ◽  
Data Generation ◽  
Efficient Treatment

Analysis and systematization of accumulated data on carbohydrate structural diversity is a subject of great interest for structural glycobiology. Despite being a challenging task, development of computational methods for efficient treatment and management of spatial (3D) structural features of carbohydrates breaks new ground in modern glycoscience. This review is dedicated to approaches of chemo- and glyco-informatics towards 3D structural data generation, deposition and processing in regard to carbohydrates and their derivatives. Databases, molecular modeling and experimental data validation services, and structure visualization facilities developed for last five years are reviewed.

Elucidating sequence and solvent specific design targets to protect and stabilize enzymes for biocatalysis in ionic liquids

2017 ◽  
Vol 19 (26) ◽  
pp. 17426-17433 ◽  
Author(s):  
K. G. Sprenger ◽  
J. G. Plaks ◽  
J. L. Kaar ◽  
J. Pfaendtner
Keyword(s):  
Ionic Liquids ◽  
Structure Function ◽  
Molecular Level ◽  
Specific Design ◽  
Host Environment ◽  
Host Interactions

For many different frameworks, the structure, function, and dynamics of an enzyme is largely determined by the nature of its interactions with the surrounding host environment, thus a molecular level understanding of enzyme/host interactions is essential to the design of new processes and applications.

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