scholarly journals Explanation of Structure and Function of kv1.3 Potent Blocker From Mesobuthus eupeus Venom Gland: A New Promise in Drug Development

2022 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Mohammad Javad Khodayar ◽  
Masoud Mahdavinia ◽  
Masoumeh Baradaran ◽  
Amir Jalali
Keyword(s):  
Conformational Changes ◽  
Three Dimensional ◽  
Venom Gland ◽  
Scorpion Venom ◽  
Protein Docking ◽  
Structure And Function ◽  
Dynamic Simulations ◽  
And Function ◽  
Key Residues ◽  
Β Sheet

Background: Scorpions and other venomous animals are sought with great concern because venom is a source of novel peptides with exciting features. Some toxins of scorpion venom are effectors of potassium channels. Previous studies strongly support the importance of potassium channel toxins for use as pharmacological tools or potential drugs. Objectives: Here, a three-dimensional (3-D) structure and function of a potent acidic blocker of the human voltage-gated potassium ion channel, Kv1.3, previously identified in the scorpion Mesobuthus eupeus venom gland, were interpreted. Methods: The 3-D structure of meuK2-2 was generated using homology modeling. The interaction of meuK2-2 with the Kv1.3 channel was evaluated using a computational protocol employing peptide-protein docking experiments, pose clustering, and 100 ns molecular dynamic simulations to make the 3-D models of the meuK2-2/Kv1.3 complex trustworthy. Results: A CSα/β (cysteine-stabilized α-helical and β-sheet) fold was found for the 3-D structure of meuK2-2. In a different mechanism from what was identified so far, meuK2-2 binds to both turret and pore loop of Kv1.3 through two key residues (Ala28 and Ser11) and H-bonds. The binding of meuK2-2 induces some conformational changes to Kv1.3. Eventually, the side chain of a positively charged amino acid (His9) occupies the channel's pore. All together blocks the ion permeation pathway. Conclusions: MeuK2-2 could block Kv1.3 by a new mechanism. So, it could be a unique target for further investigations to develop a pharmacological tool and potential drug.

Metal bridges to probe membrane ion channel structure and function

2015 ◽  
Vol 6 (3) ◽  
pp. 191-203 ◽  
Author(s):  
Paul Linsdell
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Conformational Changes ◽  
Three Dimensional ◽  
Structure And Function ◽  
Side Chains ◽  
Channel Protein ◽  
Conformational Rearrangements ◽  
And Function ◽  
Different Parts

AbstractIon channels are integral membrane proteins that undergo important conformational changes as they open and close to control transmembrane flux of different ions. The molecular underpinnings of these dynamic conformational rearrangements are difficult to ascertain using current structural methods. Several functional approaches have been used to understand two- and three-dimensional dynamic structures of ion channels, based on the reactivity of the cysteine side-chain. Two-dimensional structural rearrangements, such as changes in the accessibility of different parts of the channel protein to the bulk solution on either side of the membrane, are used to define movements within the permeation pathway, such as those that open and close ion channel gates. Three-dimensional rearrangements – in which two different parts of the channel protein change their proximity during conformational changes – are probed by cross-linking or bridging together two cysteine side-chains. Particularly useful in this regard are so-called metal bridges formed when two or more cysteine side-chains form a high-affinity binding site for metal ions such as Cd2+ or Zn2+. This review describes the use of these different techniques for the study of ion channel dynamic structure and function, including a comprehensive review of the different kinds of conformational rearrangements that have been studied in different channel types via the identification of intra-molecular metal bridges. Factors that influence the affinities and conformational sensitivities of these metal bridges, as well as the kinds of structural inferences that can be drawn from these studies, are also discussed.

Structure and function of neural networks in the retina

1988 ◽  
Vol 46 ◽  
pp. 26-27
Author(s):  
Peter Sterling
Keyword(s):  
Ganglion Cells ◽  
Three Dimensional ◽  
Structure And Function ◽  
Synaptic Connections ◽  
Visual Axis ◽  
One Dimensional ◽  
Cat Retina ◽  
Ultrathin Sections ◽  
And Function ◽  
Insight Into

The synaptic connections in cat retina that link photoreceptors to ganglion cells have been analyzed quantitatively. Our approach has been to prepare serial, ultrathin sections and photograph en montage at low magnification (˜2000X) in the electron microscope. Six series, 100-300 sections long, have been prepared over the last decade. They derive from different cats but always from the same region of retina, about one degree from the center of the visual axis. The material has been analyzed by reconstructing adjacent neurons in each array and then identifying systematically the synaptic connections between arrays. Most reconstructions were done manually by tracing the outlines of processes in successive sections onto acetate sheets aligned on a cartoonist's jig. The tracings were then digitized, stacked by computer, and printed with the hidden lines removed. The results have provided rather than the usual one-dimensional account of pathways, a three-dimensional account of circuits. From this has emerged insight into the functional architecture.

scholarly journals Impact of genetic variation on three dimensional structure and function of proteins

PLoS ONE ◽  
2017 ◽  
Vol 12 (3) ◽  
pp. e0171355 ◽  
Author(s):  
Roshni Bhattacharya ◽  
Peter W. Rose ◽  
Stephen K. Burley ◽  
Andreas Prlić
Keyword(s):  
Genetic Variation ◽  
Three Dimensional ◽  
Structure And Function ◽  
Dimensional Structure ◽  
Three Dimensional Structure ◽  
And Function

Effect of EPS on biofilm structure and function as revealed by an individual-based model of biofilm growth

2001 ◽  
Vol 43 (6) ◽  
pp. 135-135 ◽  
Author(s):  
J.-U. Kreft ◽  
J. W. Wimpenny
Keyword(s):  
Dimensional Space ◽  
Three Dimensional ◽  
Structure And Function ◽  
Individual Based Model ◽  
Biofilm Growth ◽  
Rate Dependent ◽  
Binding Forces ◽  
The Individual ◽  
And Function ◽  
Biofilm Structure

We have simulated a nitrifying biofilm with one ammonia and one nitrite oxidising species in order to elucidate the effect of various extracellular polymeric substance (EPS) production scenarios on biofilm structure and function. The individual-based model (IbM) BacSim simulates diffusion of all substrates on a two-dimensional lattice. Each bacterium is individually simulated as a sphere of given size in a continuous, three-dimensional space. EPS production kinetics was described by a growth rate dependent and an independent term (Luedeking-Piret equation). The structure of the biofilm was dramatically influenced by EPS production or capsule formation. EPS production decreased growth of producers and stimulated growth of non-producers because of the energy cost involved. For the same reason, EPS accumulation can fall as its rate of production increases. The patchiness and roughness of the biofilm decreased and the porosity increased due to EPS production. EPS density was maximal in the middle of the vertical profile. Introduction of binding forces between like cells increased clustering.

scholarly journals Conserved Structure and Function in the Granulysin and NK-Lysin Peptide Family

2005 ◽  
Vol 73 (10) ◽  
pp. 6332-6339 ◽  
Author(s):  
Charlotte M. A. Linde ◽  
Susanna Grundström ◽  
Erik Nordling ◽  
Essam Refai ◽  
Patrick J. Brennan ◽  
...  
Keyword(s):  
Mycobacterium Smegmatis ◽  
Three Dimensional ◽  
Antimycobacterial Activity ◽  
Structure And Function ◽  
Loop Structure ◽  
E Coli ◽  
Short Loop ◽  
Peptide Family ◽  
And Function ◽  
Related Proteins

ABSTRACT Granulysin and NK-lysin are homologous bactericidal proteins with a moderate residue identity (35%), both of which have antimycobacterial activity. Short loop peptides derived from the antimycobacterial domains of granulysin, NK-lysin, and a putative chicken NK-lysin were examined and shown to have comparable antimycobacterial but variable Escherichia coli activities. The known structure of the NK-lysin loop peptide was used to predict the structure of the equivalent peptides of granulysin and chicken NK-lysin by homology modeling. The last two adopted a secondary structure almost identical to that of NK-lysin. All three peptides form very similar three-dimensional (3-D) architectures in which the important basic residues assume the same positions in space. The basic residues in granulysin are arginine, while those in NK-lysin and chicken NK-lysin are a mixture of arginine and lysine. We altered the ratio of arginine to lysine in the granulysin fragment to examine the importance of basic residues for antimycobacterial activity. The alteration of the amino acids reduced the activity against E. coli to a larger extent than that against Mycobacterium smegmatis. In granulysin, the arginines in the loop structure are not crucial for antimycobacterial activity but are important for cytotoxicity. We suggest that the antibacterial domains of the related proteins granulysin, NK-lysin, and chicken NK-lysin have conserved their 3-D structure and their function against mycobacteria.

scholarly journals Structural Features of a Bacteroidetes-Affiliated Cellulase Linked with a Polysaccharide Utilization Locus

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
A.E. Naas ◽  
A.K. MacKenzie ◽  
B. Dalhus ◽  
V.G.H. Eijsink ◽  
P.B. Pope
Keyword(s):  
Active Site ◽  
Three Dimensional ◽  
Structural Features ◽  
Structure And Function ◽  
Dimensional Structure ◽  
Active Site Cleft ◽  
Polysaccharide Utilization Locus ◽  
And Function ◽  
Rumen Metagenome

Abstract Previous gene-centric analysis of a cow rumen metagenome revealed the first potentially cellulolytic polysaccharide utilization locus, of which the main catalytic enzyme (AC2aCel5A) was identified as a glycoside hydrolase (GH) family 5 endo-cellulase. Here we present the 1.8 Å three-dimensional structure of AC2aCel5A and characterization of its enzymatic activities. The enzyme possesses the archetypical (β/α)8-barrel found throughout the GH5 family and contains the two strictly conserved catalytic glutamates located at the C-terminal ends of β-strands 4 and 7. The enzyme is active on insoluble cellulose and acts exclusively on linear β-(1,4)-linked glucans. Co-crystallization of a catalytically inactive mutant with substrate yielded a 2.4 Å structure showing cellotriose bound in the −3 to −1 subsites. Additional electron density was observed between Trp178 and Trp254, two residues that form a hydrophobic “clamp”, potentially interacting with sugars at the +1 and +2 subsites. The enzyme’s active-site cleft was narrower compared to the closest structural relatives, which in contrast to AC2aCel5A, are also active on xylans, mannans and/or xyloglucans. Interestingly, the structure and function of this enzyme seem adapted to less-substituted substrates such as cellulose, presumably due to the insufficient space to accommodate the side-chains of branched glucans in the active-site cleft.

Individual Differences Among Users

2011 ◽  
pp. 1-24 ◽  
Author(s):  
Madeleine Keehner ◽  
Peter Khooshabeh ◽  
Mary Hegarty
Keyword(s):  
Individual Differences ◽  
Three Dimensional ◽  
Structure And Function ◽  
Science Literature ◽  
Interactive Behavior ◽  
Different Types ◽  
Interactive Visualizations ◽  
Cognitive Benefits ◽  
Sophisticated User ◽  
And Function

This chapter examines human factors associated with using interactive three-dimensional (3D) visualizations. Virtual representations of anatomical structure and function, often with sophisticated user control capabilities, are growing in popularity in medicine for education, training, and simulation. This chapter reviews the cognitive science literature and introduces issues such as theoretical ideas related to using interactive visualizations, different types and levels of interactivity, effects of different kinds of control interfaces, and potential cognitive benefits of these tools. The authors raise the question of whether all individuals are equally capable of using 3D visualizations effectively, focusing particularly on two variables: (1) individual differences in spatial abilities, and (2) individual differences in interactive behavior. The chapter draws together findings from the authors’ own studies and from the wider literature, exploring recent insights into how individual differences among users can impact the effectiveness of different types of external visualizations for different kinds of tasks. The chapter offers recommendations for design, such as providing transparent affordances to support users’ meta-cognitive understanding, and employing personalization to complement the capabilities of different individuals. Finally, the authors suggest future directions and approaches for research, including the use of methodology such as needs analysis and contextual enquiry to better understand the cognitive processes and capacities of different kinds of users.

scholarly journals Susceptibility of protein therapeutics to spontaneous chemical modifications by oxidation, cyclization, and elimination reactions

Amino Acids ◽  
2019 ◽  
Vol 51 (10-12) ◽  
pp. 1409-1431 ◽  
Author(s):  
Luigi Grassi ◽  
Chiara Cabrele
Keyword(s):  
Small Molecules ◽  
Three Dimensional ◽  
Drug Market ◽  
Structure And Function ◽  
Dimensional Structure ◽  
Chemical Modifications ◽  
Small Molecule Drugs ◽  
And Function ◽  
The Impact

Abstract Peptides and proteins are preponderantly emerging in the drug market, as shown by the increasing number of biopharmaceutics already approved or under development. Biomolecules like recombinant monoclonal antibodies have high therapeutic efficacy and offer a valuable alternative to small-molecule drugs. However, due to their complex three-dimensional structure and the presence of many functional groups, the occurrence of spontaneous conformational and chemical changes is much higher for peptides and proteins than for small molecules. The characterization of biotherapeutics with modern and sophisticated analytical methods has revealed the presence of contaminants that mainly arise from oxidation- and elimination-prone amino-acid side chains. This review focuses on protein chemical modifications that may take place during storage due to (1) oxidation (methionine, cysteine, histidine, tyrosine, tryptophan, and phenylalanine), (2) intra- and inter-residue cyclization (aspartic and glutamic acid, asparagine, glutamine, N-terminal dipeptidyl motifs), and (3) β-elimination (serine, threonine, cysteine, cystine) reactions. It also includes some examples of the impact of such modifications on protein structure and function.

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