The H-factor as a novel quality metric for homology modeling

BACKGROUND: Drug discovery typically starts with the identification of a potential target that is then tested and validated either through high-throughput screening against a library of drug compounds or by rational drug design. When the putative target is a protein, the latter approach requires the knowledge of its structure. Finding the structure of a protein is however a difficult task. Significant progress has come from high-resolution techniques such as X-ray crystallography and NMR; there are many proteins however whose structure have not yet been solved. Computational techniques for structure prediction are viable alternatives to experimental techniques for these cases. However, the proper validation of the structural models they generate remains an issue. FINDINGS: In this report, we focus on homology modeling techniques and introduce the H-factor, a new indicator for assessing the quality of protein structure models generated with these techniques. The H-factor is meant to mimic the R-factor used in X-ray crystallography. The method for computing the H-factor is fully described with a demonstration of its effectiveness on a test set of target proteins. CONCLUSIONS: We have developed a web service for computing the H-factor for models of a protein structure. This service is freely accessible at http://koehllab.genomecenter.ucdavis.edu/toolkit/h-factor

Pancreatic Cancer Research beyond DNA Mutations

Pancreatic ductal adenocarcinoma (PDAC) is caused by genetic mutations in four genes: KRAS proto-oncogene and GTPase (KRAS), tumor protein P53 (TP53), cyclin-dependent kinase inhibitor 2A (CDKN2A), and mothers against decapentaplegic homolog 4 (SMAD4), also called the big 4. The changes in tumors are very complex, making their characterization in the early stages challenging. Therefore, the development of innovative therapeutic approaches is desirable. The key to overcoming PDAC is diagnosing it in the early stages. Therefore, recent studies have investigated the multifaced characteristics of PDAC, which includes cancer cell metabolism, mesenchymal cells including cancer-associated fibroblasts and immune cells, and metagenomics, which extend to characterize various biomolecules including RNAs and volatile organic compounds. Various alterations in the KRAS-dependent as well as KRAS-independent pathways are involved in the refractoriness of PDAC. The optimal combination of these new technologies is expected to help treat intractable pancreatic cancer

A quality metric for homology modeling: the H-factor

<p>Abstract</p> <p>Background</p> <p>The analysis of protein structures provides fundamental insight into most biochemical functions and consequently into the cause and possible treatment of diseases. As the structures of most known proteins cannot be solved experimentally for technical or sometimes simply for time constraints, <it>in silico </it>protein structure prediction is expected to step in and generate a more complete picture of the protein structure universe. Molecular modeling of protein structures is a fast growing field and tremendous works have been done since the publication of the very first model. The growth of modeling techniques and more specifically of those that rely on the existing experimental knowledge of protein structures is intimately linked to the developments of high resolution, experimental techniques such as NMR, X-ray crystallography and electron microscopy. This strong connection between experimental and <it>in silico </it>methods is however not devoid of criticisms and concerns among modelers as well as among experimentalists.</p> <p>Results</p> <p>In this paper, we focus on homology-modeling and more specifically, we review how it is perceived by the structural biology community and what can be done to impress on the experimentalists that it can be a valuable resource to them. We review the common practices and provide a set of guidelines for building better models. For that purpose, we introduce the H-factor, a new indicator for assessing the quality of homology models, mimicking the R-factor in X-ray crystallography. The methods for computing the H-factor is fully described and validated on a series of test cases.</p> <p>Conclusions</p> <p>We have developed a web service for computing the H-factor for models of a protein structure. This service is freely accessible at <url>http://koehllab.genomecenter.ucdavis.edu/toolkit/h-factor</url>.</p

Etude in vitro du processus de repliement-oxydation de toxines courtes de scorpion actives sur les canaux potassium. Etude par modélisation moléculaire des interactions de toxines courtes de scorpion avec les canaux potassium

Ce travail de thèse comporte deux parties distinctes: (1) l'étude in vitro du processus de repliement/oxydation de toxines courtes de scorpions actives sur les canaux potassium et (2) l'étude par modélisation moléculaire des interactions entre les toxines courtes de scorpions et les canaux potassium. La problématique abordée dans la première partie est fondamentale car elle concerne l'étude des mécanismes, encore malconnus, présidant à l'acquisition de la structure native d'une protéine ou d'un peptide. Notamment, la mise en place des ponts disulfure natifs, constitue en chimie des peptides, une étape limitante à l'obtention de produits de synthèse. La première partie de mes travaux a permis d'analyser l'influence des constituants d'un milieu d'oxydation sur la cinétique de formation des ponts disulfure de peptide fortement réticulés comme la maurotoxine (MTX), en utilisant la spectrométrie de masse MALDI-TOF. Ces travaux ont été ensuite prolongés par la mise en corrélation de la formation des structures secondaires avec l'apparition des ponts disulfure et l'activité pharmacologique associée. Il se dégage alors de ces études, que les ponts disulfure se forment en synergie avec la mise en place des structures secondaires. Ces données permettent de mieux appréhender le processus de repliement/oxydation de peptides fortement réticulés comme les toxines de scorpions tout en optimisant les conditions d'obtention de molécules synthétiques.La seconde partie de ces travaux aborde les problèmes cruciaux d'arrimage moléculaire entre une toxine courte de scorpion et un canal potassique. En effet, la conception et la synthèse de peptides d'intérêt ne peuvent s'effectuer sans en étudier les mécanismes d'interaction avec leurs cibles comme les canaux potassiques. A travers l'étude des interactions entre toxines courtes de scorpions et les canaux hSKCa2 et 3, nous avons élaboré une nouvelle stratégie d'analyse par modélisation moléculaire permettant de mettre en relation une constante d'affinité expérimentale et une énergie de contact calculée. Cela permet d'obtenir, in fine, des cartes fonctionnelles d'interactions détaillées et de prédire une constante d'affinité pour une toxine sur un canal potassique. Par extension, ces études d'arrimage moléculaire ont pour objectif de rationaliser la conception de nouvelles molécules sélectives et spécifiques envers une cible donnéeAIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

C. elegans as a Powerful Tool for Cancer Screening

Regular cancer screening is critical for early cancer detection. Cancer screening tends to be burdensome, invasive, and expensive, especially for a comprehensive multi-organ check. Improving the rate and effectiveness of routine cancer screenings remain a challenge in health care. Multi-cancer early detection (MCED) is an exciting concept and a potentially effective solution for addressing current issues with routine cancer screening. In recent years, several technologies have matured for MCED, such as identifying cell-free tumor DNA in blood or using organisms such as Caenorhabditis elegans as a tool for early cancer detection. In Japan, N-NOSE is a commercially available multi-cancer detection test based on the chemotaxis of C. elegans using a urine sample showing 87.5% sensitivity and 90.2% specificity. In this review, we focus on using C. elegans as a powerful biosensor for universal cancer screening. We review N-NOSE clinical research results, spotlighting it as an effective primary cancer screening test

State-of-the-Art Cancer Biology, Biodiagnostics and Therapeutics in Japan

Early cancer detection is key to improving patient survival and quality of life and reducing cancer treatments’ financial burden [...

Pancreatic Cancer and Detection Methods

The pancreas is a vital organ with exocrine and endocrine functions. Pancreatitis is an inflammation of the pancreas caused by alcohol consumption and gallstones. This condition can heighten the risk of pancreatic cancer (PC), a challenging disease with a high mortality rate. Genetic and epigenetic factors contribute significantly to PC development, along with other risk factors. Early detection is crucial for improving PC outcomes. Diagnostic methods, including imagining modalities and tissue biopsy, aid in the detection and analysis of PC. In contrast, liquid biopsy (LB) shows promise in early tumor detection by assessing biomarkers in bodily fluids. Understanding the function of the pancreas, associated diseases, risk factors, and available diagnostic methods is essential for effective management and early PC detection. The current clinical examination of PC is challenging due to its asymptomatic early stages and limitations of highly precise diagnostics. Screening is recommended for high-risk populations and individuals with potential benign tumors. Among various PC screening methods, the N-NOSE plus pancreas test stands out with its high AUC of 0.865. Compared to other commercial products, the N-NOSE plus pancreas test offers a cost-effective solution for early detection. However, additional diagnostic tests are required for confirmation. Further research, validation, and the development of non-invasive screening methods and standardized scoring systems are crucial to enhance PC detection and improve patient outcomes. This review outlines the context of pancreatic cancer and the challenges for early detection

Crystallographic observation of pH-induced conformational changes in the Amyelois transitella pheromone-binding protein AtraPBP1.

The navel orangeworm, Amyelois transitella is a major agricultural pest causing large losses in a variety of tree crops. Control of this insect pest may be achieved by interfering with olfactory pathways to block detection of female-produced sex pheromones and consequently, disrupt mating. The first component of this pathway is the pheromone-binding protein AtraPBP1, which recognizes the pheromone and presents it to the odorant receptor housed in a sensory neuron of the male antennae. Release of the ligand depends on a pH-induced conformational change associated with the acidity of the membrane surface. To characterize this conformational change and to understand how pheromones bind, we have determined the high resolution crystal structures of AtraPBP1 in complex with two main constituents of the sex pheromone, i.e., (11Z,13Z)-hexadecadienal and (11Z,13Z)-hexadecadienol. Comparison with the structure of the unliganded form demonstrates a large ∼90° movement of the C-terminal helix which is observed in other pheromone- or odorant-binding proteins accompanied by an unpredicted 37° displacement of the N-terminal helix. Molecular dynamic trajectories suggest that the conformational change of the α1 helix facilitates the movement of the C-terminal helix