Advances in protein chemistry and structural biology最新文献

{"title":"Leveraging nuclear receptor mediated transcriptional signaling for drug discovery: Historical insights and current advances.","authors":"Riya Ben Patel, Surbhi Kumari Barnwal, Arabi Mohammed Saleh M A, Dileep Francis","doi":"10.1016/bs.apcsb.2024.10.001","DOIUrl":"10.1016/bs.apcsb.2024.10.001","url":null,"abstract":"<p><p>Nuclear receptors (NRs) are ligand-activated transcription factors that regulate gene expression in response to physiological signals, such as hormones and other chemical messengers. These receptors either activate or repress the transcription of target genes, which in turn promotes or suppresses physiological processes governing growth, differentiation, and homeostasis. NRs bind to specific DNA sequences and, in response to ligand binding, either promote or hinder the assembly of the transcriptional machinery, thereby influencing gene expression at the transcriptional level. These receptors are involved in a wide range of pathological conditions, including cancer, metabolic disorders, chronic inflammatory diseases, and immune system-related disorders. Modulation of NR function through targeted drugs has shown therapeutic benefits in treating such conditions. NR-targeted drugs, which either completely or selectively activate or block receptor function, represent a significant class of clinically valuable therapeutics. However, the pathways of NR-mediated gene expression and the resulting physiological effects are complex, involving crosstalk between various biomolecular components. As a result, NR-targeted drug discovery is challenging. With improved understanding of how NRs regulate physiological functions and deeper insights into their molecular structure, the process of NR-targeted drug discovery has evolved. While many traditional NR-targeting drugs are associated with side effects of varying severity, new drug candidates are being designed to minimize these adverse effects. Given that NR activity varies according to the tissue in which they are expressed and the specific isoform that is activated or repressed, achieving selectivity in targeting specific tissues and isoform classes may help reduce systemic side effects. In a recent breakthrough, the isoform-selective, hepato-targeted thyroid hormone-β agonist, Resmetirom (marketed as Rezdiffra), was approved for the treatment of non-alcoholic steatohepatitis. This chapter explores the structural and mechanistic principles guiding NR-targeted drug discovery and provides insights into recent developments in this field.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"143 ","pages":"191-269"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Medicinal chemistry-based novel herapeutics for Tauopathies in Alzheimer's disease.","authors":"Subashchandrabose Chinnathambi, Sneha Malik, Madhura Chandrashekar, Murugappan Kumurappan","doi":"10.1016/bs.apcsb.2024.09.001","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.09.001","url":null,"abstract":"<p><p>Research on the Alzheimer's disease (AD) has been going on for over 100 years, but there is yet to be found an effective cure that has passed all the clinical trials. However, many compounds have been explored for their effects on AD patients, compounds that could help ease the disease symptoms or help slow down the disease progression or reverse the effects of the disease. Small molecules like toluidine blue and melatonin are seen to be useful against AD. Natural compounds were seen to have an exceptional potential as therapeutics for AD. Highly branched polymers, dendrimers were also seen to be effective Tau and AD therapeutics as drug-delivery systems and on their own. Metal complexes and metal nanoparticles also showed success against AD. Synthesis of a bifunctional compound that was an effective chelating agent for Cu, useful against Tau and Amyloid-β (Aβ) and was catalysed by excess Cu metal present in association with Aβ was also done. It is necessary to take forward the effective therapeutics to further levels of clinical trials.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"147 ","pages":"151-175"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145090721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"cirCodAn: A GHMM-based tool for accurate prediction of coding regions in circRNA.","authors":"Denilson Fagundes Barbosa, Liliane Santana Oliveira, Pedro Gabriel Nachtigall, Rodolpho Valentini Junior, Nayane de Souza, Alexandre Rossi Paschoal, André Yoshiaki Kashiwabara","doi":"10.1016/bs.apcsb.2023.11.012","DOIUrl":"10.1016/bs.apcsb.2023.11.012","url":null,"abstract":"<p><p>Studies focusing on characterizing circRNAs with the potential to translate into peptides are quickly advancing. It is helping to elucidate the roles played by circRNAs in several biological processes, especially in the emergence and development of diseases. While various tools are accessible for predicting coding regions within linear sequences, none have demonstrated accurate open reading frame detection in circular sequences, such as circRNAs. Here, we present cirCodAn, a novel tool designed to predict coding regions in circRNAs. We evaluated the performance of cirCodAn using datasets of circRNAs with strong translation evidence and showed that cirCodAn outperformed the other tools available to perform a similar task. Our findings demonstrate the applicability of cirCodAn to identify coding regions in circRNAs, which reveals the potential of use of cirCodAn in future research focusing on elucidating the biological roles of circRNAs and their encoded proteins. cirCodAn is freely available at https://github.com/denilsonfbar/cirCodAn.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"139 ","pages":"289-334"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140048541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Motor proteins, spermatogenesis and testis function.","authors":"Lingling Wang, Tiao Bu, Xiaolong Wu, Linxi Li, Fei Sun, C Yan Cheng","doi":"10.1016/bs.apcsb.2024.03.003","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.03.003","url":null,"abstract":"<p><p>The role of motor proteins in supporting intracellular transports of vesicles and organelles in mammalian cells has been known for decades. On the other hand, the function of motor proteins that support spermatogenesis is also well established since the deletion of motor protein genes leads to subfertility and/or infertility. Furthermore, mutations and genetic variations of motor protein genes affect fertility in men, but also a wide range of developmental defects in humans including multiple organs besides the testis. In this review, we seek to provide a summary of microtubule and actin-dependent motor proteins based on earlier and recent findings in the field. Since these two cytoskeletons are polarized structures, different motor proteins are being used to transport cargoes to different ends of these cytoskeletons. However, their involvement in germ cell transport across the blood-testis barrier (BTB) and the epithelium of the seminiferous tubules remains relatively unknown. It is based on recent findings in the field, we have provided a hypothetical model by which motor proteins are being used to support germ cell transport across the BTB and the seminiferous epithelium during the epithelial cycle of spermatogenesis. In our discussion, we have highlighted the areas of research that deserve attention to bridge the gap of research in relating the function of motor proteins to spermatogenesis.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"141 ","pages":"381-445"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141496831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The crosstalk between extracellular matrix proteins and Tau.","authors":"Subashchandrabose Chinnathambi, Smita Eknath Desale","doi":"10.1016/bs.apcsb.2024.04.002","DOIUrl":"10.1016/bs.apcsb.2024.04.002","url":null,"abstract":"<p><p>Alzheimer's disease is progressive neurodegenerative disease characterize by the presence of extracellular accumulation of amyloid-β plaques and intracellular deposits of neurofibrillary tangles of Tau. Apart from axonal depositions pathological aggregated Tau protein is known to secrete into extracellular spaces and propagate through seeding mechanism. Microglia, the immune cells of the brain display modest ability to internalize the extracellular Tau and degrade it through endolysosomal pathway. However, the excessive burden of pathoproteins weakens the phagocytic ability of microglia. Extracellular supplementation of omega-3 fatty acids (n-3) may regulate the phagocytosis of microglia as they mediate the anti-inflammatory polarization of microglia through membrane lipid compositions changes. The internalization of extracellular Tau in the microglia is regulated by cortical membrane-associated actin remodeling driven by interplay of actin-binding proteins. On the other hand, Tau display capability bind and interact with various actin-binding protein owing to the presence of proline-rich domain in the structure and regulate their activation. In this study, we hypothesize that internalization of Tau in the presence of omega-3 fatty acids would propagate the Tau-mediated activation of actin-binding proteins as well as extracellular matrix and in turn modulate cortical actin remodeling for phagocytosis.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"141 ","pages":"447-466"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141496833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic applications in identifying protein-protein interactions.","authors":"Benjamin T Veenstra, Timothy D Veenstra","doi":"10.1016/bs.apcsb.2023.04.001","DOIUrl":"10.1016/bs.apcsb.2023.04.001","url":null,"abstract":"<p><p>There are many things that can be used to characterize a protein. Size, isoelectric point, hydrophobicity, structure (primary to quaternary), and subcellular location are just a few parameters that are used. The most important feature of a protein, however, is its function. While there are many experiments that can indicate a protein's role, identifying the molecules it interacts with is probably the most definitive way of determining its function. Owing to technology limitations, protein interactions have historically been identified on a one molecule per experiment basis. The advent of high throughput multiplexed proteomic technologies in the 1990s, however, made identifying hundreds and thousands of proteins interactions within single experiments feasible. These proteomic technologies have dramatically increased the rate at which protein-protein interactions (PPIs) are discovered. While the improvement in mass spectrometry technology was an early driving force in the rapid pace of identifying PPIs, advances in sample preparation and chromatography have recently been propelling the field. In this chapter, we will discuss the importance of identifying PPIs and describe current state-of-the-art technologies that demonstrate what is currently possible in this important area of biological research.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"138 ","pages":"1-48"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139465968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overlapping action of melatonin and female reproductive hormones-Understand the impact in pregnancy and menopause.","authors":"Rafael Mineiro, Maria Rodrigues Cardoso, João Vieira Pinheiro, José Cipolla-Neto, Fernanda Gaspar do Amaral, Telma Quintela","doi":"10.1016/bs.apcsb.2024.06.005","DOIUrl":"10.1016/bs.apcsb.2024.06.005","url":null,"abstract":"<p><p>Melatonin is an indolamine secreted to circulation by the pineal gland according to a circadian rhythm. Melatonin levels are higher during nighttime, and the principal function of this hormone is to organize the temporal night and day distribution of physiological adaptive processes. Besides hormonal pineal production, melatonin is synthesized in various organs and tissues like the ovaries or the placenta for local utilization. In addition to its function as a circadian messenger, melatonin is also associated with many physiological functions. For example, melatonin has antioxidant properties and is involved in the regulation of energy and bone metabolism, and reproduction. Melatonin impacts several stages of reproduction and the action across the hypothalamus-pituitary-gonadal axis is well described. However, it is not well understood how those actions impact the female reproductive hormones secretion nor the consequent physiological outcomes. Thus, the first part of this chapter describes the regulation of female reproductive hormone synthesis by melatonin. Moreover, melatonin and female reproductive hormones have coincident physiological functions. Life stages like pregnancy or menopause are characterized by alterations in the reproductive hormones secretion that may be associated with certain physiological stages. Therefore, the second part discusses whether melatonin fluctuations could have an overlapping role with reproductive hormones in contributing to clinical outcomes associated with pregnancy and menopause.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"142 ","pages":"163-190"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141764734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomarker identification of medullary thyroid carcinoma from gene expression profiles considering without-treatment and with-treatment studies-A bioinformatics approach.","authors":"Tamizhini Loganathan, C George Priya Doss","doi":"10.1016/bs.apcsb.2023.12.011","DOIUrl":"10.1016/bs.apcsb.2023.12.011","url":null,"abstract":"<p><p>Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor derived from parafollicular thyroid gland cells. In both hereditary MTC and sporadic forms, genetic changes result in fundamental changes, and prognosis and mutational status are highly correlated. In this work, biomarker genes (DEGs and DEmiRNAs) for MTC will be computationally identified in order to help in their diagnosis and treatment. The gene expression profiles of two different types of studies, namely without-treatment (wo-trt) and with-treatment (w-trt), are considered for discovering biomarkers. The datasets were retrieved from the GEO database, and the DEGs and DEmiRNAs were analyzed using ExpressAnalyst and GEO2R. The functional analysis of DEGs and DEmiRNAs was performed, and most of the pathways enriched related to thyroid oncological pathways such as MAPK pathway,mTOR pathway, and PI3K-AKT Signaling pathway. Through this conclusion, the RET gene was upregulated wo-trt; the dinaciclib treatment RET gene was down-regulated computationally. To optimize the therapeutic targeting of RET, greater research into the mechanisms regulating RET transcription is necessary.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"142 ","pages":"367-396"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141764727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico network pharmacology study on Glycyrrhiza glabra: Analyzing the immune-boosting phytochemical properties of Siddha medicinal plant against COVID-19.","authors":"Karthik Sekaran, Ashwini Karthik, Rinku Polachirakkal Varghese, P Sathiyarajeswaran, M S Shree Devi, R Siva, C George Priya Doss","doi":"10.1016/bs.apcsb.2023.04.003","DOIUrl":"10.1016/bs.apcsb.2023.04.003","url":null,"abstract":"<p><p>Immunosenescence is a pertinent factor in the mortality rate caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The changes in the immune system are strongly associated with age and provoke the deterioration of the individual's health. Traditional medical practices in ancient India effectively deal with COVID-19 by boosting natural immunity through medicinal plants. The anti-inflammatory and antiviral properties of Glycyrrhiza glabra are potent in fighting against COVID-19 and promote immunity boost against the severity of the infection. Athimadhura Chooranam, a polyherbal formulation containing Glycyrrhiza glabra as the main ingredient, is recommended as an antiviral Siddha herb by the Ministry of AYUSH. This paper is intended to identify the phytoconstituents of Glycyrrhiza glabra that are actively involved in preventing individuals from COVID-19 transmission. The modulated pathways, enrichment study, and drug-likeness are calculated from the target proteins of the phytoconstituents at the pharmacological activity (Pa) of more than 0.7. Liquiritigenin and Isoliquiritin, the natural compounds in Glycyrrhiza glabra, belong to the flavonoid class and exhibit ameliorative effects against COVID-19. The latter compound displays a higher protein interaction to a maximum of six, out of which HMOX1, PLAU, and PGR are top-hub genes. ADMET screening further confirms the significance of the abovementioned components containing better drug-likeness. The molecular docking and molecular dynamics method identified liquiritigenin as a possible lead molecule capable of inhibiting the activity of the major protease protein of SARS-CoV-2. The findings emphasize the importance of in silico network pharmacological assessments in delivering cost-effective, time-bound clinical drugs.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"1 1","pages":"233-255"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10275734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48717751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiomics data identifies RSPO2 as a prognostic biomarker in human tumors associated with pan-cancer.","authors":"Ankit Srivastava, Sameer Srivastava","doi":"10.1016/bs.apcsb.2023.11.011","DOIUrl":"10.1016/bs.apcsb.2023.11.011","url":null,"abstract":"<p><p>RSPO2 protein may provide valuable insights into the mechanism underlying various types of tumorigenesis. The role of RSPO2 in pan-cancer has not been reported so far. Therefore, this study aimed to provide a comprehensive analysis of RSPO2 from a pan-cancer perspective employing multiomics data. The expression profile and function of RSPO2 across different tumors were investigated using various web-based tools UALCAN, GEPIA, TIMER, Human Protein Atlas, cBioPortal, TISIDB, STRING, and Metascape to interpret the expression profile, promoter methylation status, genomic alterations, survival analysis, protein-protein interaction, correlation with immune cell subtypes, tumor immune microenvironment and enrichment analysis. Comprehensive pan-cancer analysis indicated that RSPO2 was significantly downregulated in eleven and upregulated in five tumor types compared to normal tissues, validation results further suggest RSPO2 was downregulated in most of the tumors. The protein level expression of RSPO2 was mostly low in malignant tissues. We found that RSPO2 was significantly related to individual pathological stages in BLCA, COAD, LUAD and LUSC. Prognostic analysis indicates that the high RSPO2 expression was significantly correlated with the poor prognosis in BRCA, KICH, KIRP, READ, and UCES. Furthermore, RSPO2 is frequently amplified, exhibits hypermethylated promoter in most cancers, and is associated with immune subtypes, molecular subtypes and immune cell infiltration. Finally, enrichment analysis showed that RSPO2 is involved in the regulation of the canonical Wnt pathway and neuronal development. The overall comprehensive pan-cancer analysis affirms that RSPO2 could be a promising diagnostic and prognostic biomarker and latent therapy target in the future.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"139 ","pages":"469-499"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140048546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}