Structure-based Functions Research Articles

Design Strategies of Tumor-Targeted Delivery Systems Based on 2D Nanomaterials.

Conventional chemotherapy and radiotherapy are nonselective and nonspecific for cell killing, causing serious side effects and threatening the lives of patients. It is of great significance to develop more accurate tumor-targeting therapeutic strategies. Nanotechnology is in a leading position to provide new treatment options for cancer, and it has great potential for selective targeted therapy and controlled drug release. 2D nanomaterials (2D NMs) have broad application prospects in the field of tumor-targeted delivery systems due to their special structure-based functions and excellent optical, electrical, and thermal properties. This review emphasizes the design strategies of tumor-targeted delivery systems based on 2D NMs from three aspects: passive targeting, active targeting, and tumor-microenvironment targeting, in order to promote the rational application of 2D NMs in clinical practice.

Advances on Delivery of Cytotoxic Enzymes as Anticancer Agents.

Cancer is one of the most serious human diseases, causing millions of deaths worldwide annually, and, therefore, it is one of the most investigated research disciplines. Developing efficient anticancer tools includes studying the effects of different natural enzymes of plant and microbial origin on tumor cells. The development of various smart delivery systems based on enzyme drugs has been conducted for more than two decades. Some of these delivery systems have been developed to the point that they have reached clinical stages, and a few have even found application in selected cancer treatments. Various biological, chemical, and physical approaches have been utilized to enhance their efficiencies by improving their delivery and targeting. In this paper, we review advanced delivery systems for enzyme drugs for use in cancer therapy. Their structure-based functions, mechanisms of action, fused forms with other peptides in terms of targeting and penetration, and other main results from in vivo and clinical studies of these advanced delivery systems are highlighted.

Prediction and Modeling of Protein-Protein Interactions Using "Spotted" Peptides with a Template-Based Approach.

Protein–peptide interactions (PpIs) are a subset of the overall protein–protein interaction (PPI) network in the living cell and are pivotal for the majority of cell processes and functions. High-throughput methods to detect PpIs and PPIs usually require time and costs that are not always affordable. Therefore, reliable in silico predictions represent a valid and effective alternative. In this work, a new algorithm is described, implemented in a freely available tool, i.e., “PepThreader”, to carry out PPIs and PpIs prediction and analysis. PepThreader threads multiple fragments derived from a full-length protein sequence (or from a peptide library) onto a second template peptide, in complex with a protein target, “spotting” the potential binding peptides and ranking them according to a sequence-based and structure-based threading score. The threading algorithm first makes use of a scoring function that is based on peptides sequence similarity. Then, a rerank of the initial hits is performed, according to structure-based scoring functions. PepThreader has been benchmarked on a dataset of 292 protein–peptide complexes that were collected from existing databases of experimentally determined protein–peptide interactions. An accuracy of 80%, when considering the top predicted 25 hits, was achieved, which performs in a comparable way with the other state-of-art tools in PPIs and PpIs modeling. Nonetheless, PepThreader is unique in that it is able at the same time to spot a binding peptide within a full-length sequence involved in PPI and model its structure within the receptor. Therefore, PepThreader adds to the already-available tools supporting the experimental PPIs and PpIs identification and characterization.

Carboxylic Ester Hydrolases in Bacteria: Active Site, Structure, Function and Application

Carboxylic ester hydrolases (CEHs), which catalyze the hydrolysis of carboxylic esters to produce alcohol and acid, are identified in three domains of life. In the Protein Data Bank (PDB), 136 crystal structures of bacterial CEHs (424 PDB codes) from 52 genera and metagenome have been reported. In this review, we categorize these structures based on catalytic machinery, structure and substrate specificity to provide a comprehensive understanding of the bacterial CEHs. CEHs use Ser, Asp or water as a nucleophile to drive diverse catalytic machinery. The α/β/α sandwich architecture is most frequently found in CEHs, but 3-solenoid, β-barrel, up-down bundle, α/β/β/α 4-layer sandwich, 6 or 7 propeller and α/β barrel architectures are also found in these CEHs. Most are substrate-specific to various esters with types of head group and lengths of the acyl chain, but some CEHs exhibit peptidase or lactamase activities. CEHs are widely used in industrial applications, and are the objects of research in structure- or mutation-based protein engineering. Structural studies of CEHs are still necessary for understanding their biological roles, identifying their structure-based functions and structure-based engineering and their potential industrial applications.

Radiation Pressure Induced Hierarchical Structure of Liquid Crystalline Inorganic Nanosheets

Although hierarchical assemblies of colloidal particles add novel structure-based functions to systems, few local and on-demand colloidal structures have been developed. We have combined the colloidal liquid crystallinity of two-dimensional inorganic particles and laser radiation pressure to obtain a large hierarchical and local structure in a colloidal system. The scattering force of the laser beam converted the parallel nanosheet alignment to the direction of the incident laser beam. At the focal point, the nanosheet orientation depends on the electric field of the polarized laser beam. In contrast, a giant tree-ring-like nanosheet texture of more than 100 μm, and which is independent of the polarization direction, was organized at the periphery of the focal point. This organization resulted from a cooperative effect between the liquid-crystalline nanosheets, which indicates an effectiveness of optical manipulation to construct hierarchical colloidal structures with the aid of interparticle interactions.

Injectable and 3D Bioprinted Polysaccharide Hydrogels: From Cartilage to Osteochondral Tissue Engineering.

Biomechanical performance of functional cartilage is executed by the exclusive anisotropic composition and spatially varying intricate architecture in articulating ends of diarthrodial joint. Osteochondral tissue constituting the articulating ends comprise superfical soft cartilage over hard subchondral bone sandwiching interfacial soft-hard tissue. The shock-absorbent, lubricating property of cartilage and mechanical stability of subchondral bone regions are rendered by extended chemical structure of glycosaminoglycans and mineral deposition, respectively. Extracellular matrix glycosaminoglycans analogous polysaccharides are major class of hydrogels investigated for restoration of functional cartilage. Recently, injectable hydrogels have gained momentum as it offers patient compliance, tunable mechanical properties, cell deliverability, and facile administration at physiological condition with long-term functionality and hyaline cartilage construction. Interestingly, facile modifiable functional groups in carbohydrate polymers impart tailorability of desired physicochemical properties and versatile injectable chemistry for the development of highly potent biomimetic in situ forming scaffold. The scaffold design strategies have also evolved from single component to bi- or multilayered and graded constructs with osteogenic properties for deep subchondral regeneration. This review highlights the significance of polysaccharide structure-based functions in engineering cartilage tissue, injectable chemistries, strategies for combining analogous matrices with cells/stem cells and biomolecules and multicomponent approaches for osteochondral mimetic constructs. Further, the rheology and precise spatiotemporal positioning of cells in hydrogel bioink for rapid prototyping of complex three-dimensional anisotropic cartilage have also been discussed.

Structural modeling of ataxin-3 reveals distant homology to adaptins.

Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine disorder caused by a CAG repeat expansion in the coding region of a gene encoding ataxin-3, a protein of yet unknown function. Based on a comprehensive computational analysis, we propose a structural model and structure-based functions for ataxin-3. Our predictive strategy comprises the compilation of multiple sequence and structure alignments of carefully selected proteins related to ataxin-3. These alignments are consistent with additional information on sequence motifs, secondary structure, and domain architectures. The application of complementary methods revealed the homology of ataxin-3 to ENTH and VHS domain proteins involved in membrane trafficking and regulatory adaptor functions. We modeled the structure of ataxin-3 using the adaptin AP180 as a template and assessed the reliability of the model by comparison with known sequence and structural features. We could further infer potential functions of ataxin-3 in agreement with known experimental data. Our database searches also identified an as yet uncharacterized family of proteins, which we named josephins because of their pronounced homology to the Josephin domain of ataxin-3.

Access to Mathematics for Visually Disabled Students Through Multimodal Interaction

Mathematics relies on visual forms of communication and is thus largely inaccessible to people who cannot communicate in this manner because of visual disabilities. This article outlines the Mathtalk project, which addressed this problem by using computers to produce multimodal renderings of mathematical information. This example is unusual in that it is essential to use multiple modalities because of the nature and the difficulty of the application. In addition, the emphasis is on nonvisual (and hence novel) modalities. Crucial to designing a usable auditory interface to algebra notation is an understanding of the differences between visual and listening reading, particularly those aspects that make the former active and the latter passive. A discussion of these differences yields the twin themes of compensation for lack of external memory and provision of control over information flow. These themes were addressed by: the introduction of prosody to convey algebraic structure in synthetically spoken expressions; the provision of structure-based browsing functions; and the use of a prosody-based musical glance based on algebra earcons. The addition of prosody, when compared to a traditional method of presenting spoken algebra, was experimentally shown to increase the recovery of algebraic structure, enhance the retention of content, and reduce mental workload. These three factors can be said to compensate for the lack of an adequate external memory. Evaluations showed that the browsing functions and associated command language gave the fast and accurate control over information flow that is necessary for active reading. The algebra earcon was experimentally shown to convey the presence, location, and size of algebraic constructs within an expression in a manner that might be used as a rapid glance. Finally, an evaluation of the integrated components showed that the design principles derived from the Mathtalk program can give a more usable, active reading of algebra notation than that possible with traditional methods.