Advances in protein chemistry and structural biology最新文献

{"title":"How to accurately predict nanobody structure: Classical physics-based simulations or deep learning approaches.","authors":"Hongyan Yu, Binbin Xu, Feng Zhan, Weiwei Xue","doi":"10.1016/bs.apcsb.2024.12.001","DOIUrl":"10.1016/bs.apcsb.2024.12.001","url":null,"abstract":"<p><p>Antibodies are important functional proteins widely used in the prevention, diagnosis, and treatment of diseases. Heavy-chain single-domain antibodies (VHHs) derived from camels, also known as nanobodies (Nbs), are gradually becoming alternative options to full-length antibodies (VHHs) due to their small molecular weight, high stability, and good affinity. The structure of Nb includes framework regions (FRs) and complementarity-determining regions (CDRs). Currently, the prediction of CDRs structures in Nbs remains a challenge. Based on the different lengths and residue arrangements of CDR3, which form different antigen-binding surfaces, Nbs can be classified into three major categories: concave, loop, and convex. In this study, we selected representative Nbs with known structures from each category (Nb32, Nb80, and Nb35) and systematically studied their structures, especially the prediction accuracy of CDR3, using two strategies: physics-based simulations (homology modeling + molecular dynamics simulation) and deep learning (AlphaFold2 and RoseTTAFold). By comparing and analyzing the prediction results with experimental structures, we provided suggestions for accurately predicting the structures of different categories of Nbs and proposed the viewpoint that the formation of the binding surface between Nbs and target proteins requires proteins through an induced fit mechanism.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"147 ","pages":"129-150"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145090785","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":"Lipids modulates Tau and amyloid-β proteins in Alzheimer's disease.","authors":"Subashchandrabose Chinnathambi, Sreeramkumar Selvakumar, Madhura Chandrashekar","doi":"10.1016/bs.apcsb.2024.08.005","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.08.005","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a multifaceted neurodegenerative condition, marked by memory loss and a steady deterioration in cognitive function. Lipid metabolism, which encompasses different lipid types such sphingolipids, cholesterol, fat-soluble vitamins, and fatty acids, is one of the key components of AD pathogenesis. These lipids are essential for many cellular functions, and the onset and course of AD are greatly influenced by their dysregulation. Sphingolipids, which include gangliosides, sulfatides, ceramides, and sphingomyelins, are essential for signal transduction, myelin sheath development, and the integrity of cell membranes. Sphingolipid metabolism is altered in AD, as seen by changes in ceramide levels and a reduction in sulfatides. These changes are associated with inflammation and neuronal death. Additionally, sphingomyelins and gangliosides are implicated; specific alterations in their concentrations have been reported in brains affected by AD, suggesting their participation in amyloid-β (Aβ) pathology and neurodegeneration.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"146 ","pages":"137-159"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558789","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":"Revolutionizing pancreatic cancer treatment with CAR-T therapy.","authors":"Kirti Baghel, Sanjana Mehrotra, Vijay Kumar Prajapati","doi":"10.1016/bs.apcsb.2024.10.008","DOIUrl":"10.1016/bs.apcsb.2024.10.008","url":null,"abstract":"<p><p>Pancreatic cancer remains one of the most lethal malignancies, with a five-year survival rate among the lowest of all cancers. This poor prognosis is largely due to the aggressive nature of the disease and its resistance to conventional treatments such as surgery, chemotherapy, and radiation therapy. Chimeric antigen receptor (CAR) T-cell therapy, a novel immunotherapeutic approach leverages the patient's own immune system to specifically target and eliminate cancer cells by genetically engineering T cells to express CARs that recognize tumor-specific antigens. While CAR-T therapy has demonstrated remarkable success in treating hematologic malignancies, its application to solid tumors like pancreatic cancer presents significant challenges. Recent advancements in CAR-T cell design, like the addition of co-stimulatory domains and dual-targeting CARs, have enhanced their efficacy against solid tumors. Additionally, strategies to modify the tumor microenvironment (TME), such as combining CAR-T therapy with immune checkpoint inhibitors and cytokine modulation, are being investigated to boost CAR-T cell activity against pancreatic cancer. Early-phase clinical trials targeting antigens such as carcinoembryonic antigen (CEA) and mesothelin (MSLN) in pancreatic cancer have yielded encouraging results, though obstacles like antigen escape and limited T-cell persistence remain significant challenges. This chapter outlines the current state of CAR-T therapy for pancreatic cancer, focusing on the emerging approaches to address these obstacles and underscore the potential of CAR-T therapy to transform the future of pancreatic cancer treatment.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"144 ","pages":"331-353"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466722","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":"Investigating the mechanisms of Plantago major and Plantago lanceolata in non-small cell lung cancer: A study of their bioactive phytocompounds through network pharmacology, molecular docking, and integrated computational approaches.","authors":"Ambritha Balasundaram, Sakshi Manoj Kamath, D Thirumal Kumar, George Priya Doss C","doi":"10.1016/bs.apcsb.2025.02.002","DOIUrl":"10.1016/bs.apcsb.2025.02.002","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) is the predominant form of lung cancer, associated with high morbidity and mortality rates. Current treatments, including surgical resection, chemotherapy, targeted therapy, and radiation, offer limited improvement in prognosis, with a low five-year survival rate. Thus, innovative therapeutic approaches are critically needed. The study utilized a network pharmacology approach to explore the phytocompounds of P. major and P. lanceolata targeting key genes in NSCLC. It involved collecting compounds of P. major and P. lanceolata using IMPPAT 2.0 and literature, screening drug-likeliness compounds using SWISS ADME, target prediction for bioactive compounds using SWISS targets, screening NSCLC-related targets using Genecards and OMIM, gene function annotation using DAVID GO and KEGG analysis, constructing a \"Compounds-Targets-Pathway\" network and analyzing protein interaction to identify hub genes using STRING and Cytoscape software, conducting molecular docking using Autodocktools and Autodock Vina, and lastly performing molecular dynamics simulations using GROMACS. Functional enrichment GO analysis and KEGG pathway analysis indicated that the primary mechanism of action of P. major and P. lanceolata phytocompounds in NSCLC treatment involves regulating cellular metabolism, survival, and cell cycle progression through various signaling pathways, including PKB, RA, PTP, hormone-mediated signaling, and PI3K. Molecular docking studies identified eight bioactive compounds with strong affinity for EGFR and three for MET, suggesting potential treatments for NSCLC with EGFR and MET mutations. Molecular dynamics simulations revealed that apigenin-7-O-glucoside is a promising therapeutic option for NSCLC with EGFR mutations, while scutellarein is more effective for MET mutations. The research provides the scientific basis for developing quality control standards and therapeutic applications, particularly for treating EGFR and MET mutations in NSCLC. It also highlights the need for further investigation into using P. major and P. lanceolata phytocompounds in NSCLC treatment.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"147 ","pages":"207-240"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145090760","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":"Protein aggregation in health and disease: A looking glass of two faces.","authors":"Guilherme C de Andrade, Michelle F Mota, Dinarte N Moreira-Ferreira, Jerson L Silva, Guilherme A P de Oliveira, Mayra A Marques","doi":"10.1016/bs.apcsb.2024.09.010","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.09.010","url":null,"abstract":"<p><p>Protein molecules organize into an intricate alphabet of twenty amino acids and five architecture levels. The jargon \"one structure, one functionality\" has been challenged, considering the amount of intrinsically disordered proteins in the human genome and the requirements of hierarchical hetero- and homo-protein complexes in cell signaling. The assembly of large protein structures in health and disease is now viewed through the lens of phase separation and transition phenomena. What drives protein misfolding and aggregation? Or, more fundamentally, what hinders proteins from maintaining their native conformations, pushing them toward aggregation? Here, we explore the principles of protein folding, phase separation, and aggregation, which hinge on crucial events such as the reorganization of solvents, the chemical properties of amino acids, and their interactions with the environment. We focus on the dynamic shifts between functional and dysfunctional states of proteins and the conditions that promote protein misfolding, often leading to disease. By exploring these processes, we highlight potential therapeutic avenues to manage protein aggregation and reduce its harmful impacts on health.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"145 ","pages":"145-217"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955662","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":"Investigation of new non-toxic inhibitors of fibril formation and preservatives for insulin preparations its analogues.","authors":"Sergei Y Grishin, Alexey K Surin, Oxana V Galzitskaya","doi":"10.1016/bs.apcsb.2024.09.013","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.09.013","url":null,"abstract":"<p><p>Insulin and its analogue formulations are the main components in the therapy of insulin-dependent forms of diabetes. Insulin and its analogues can form amyloid-like aggregates during long-term storage and local concentration increases, leading to reduced therapeutic efficacy and potential side effects such as insulin amyloidosis. The aim of this study was to identify and propose new non-toxic inhibitors and preservatives to replace phenol in insulin formulations. The peptide FVNQH and phenol red were studied as promising inhibitors of fibril formation of insulin, lispro, and glargine in vitro using the specific amyloid dye thioflavin T. The peptide FVNQH and phenol red (0.5-1 mg/mL) showed a bacteriostatic effect on the E. coli K-12 strain after 24 h. The fibril-inhibiting and antimicrobial effects of these substances were similar to the effect of phenol at a concentration of 0.5 mg/mL. Thus, the identified inhibitors can potentially replace phenolic components in slowing amyloid aggregation and increase the stability of insulin and its analogues.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"145 ","pages":"113-143"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958055","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":"Immunotherapy to CD5, a T-cell antigen having roles from development to peripheral function: Future prospective and challenges.","authors":"Ranjeet Bahadur Choubey, Sweta, Vibha, Avika Sharma, Ambak Kumar Rai","doi":"10.1016/bs.apcsb.2024.10.007","DOIUrl":"10.1016/bs.apcsb.2024.10.007","url":null,"abstract":"<p><p>CD5 is a pan T-cell marker expressed by all T-cells and a subset of B-cells, i.e., B1a cells. The significance of CD5 is evident from its functions, starting from T-cell development, antigen priming, activation, and effector response to the maintenance of tolerance. Varying CD5 expression and signaling in response to TCR-pMHC complex avidity is associated with thymic selection, competency, and effector response. Altered CD5 expression is associated with immunological and diseased conditions such as CD5^-/low infiltrating T-cells in solid tumors, CD5^hi T-cells in anergy conditions, CD5^-/low phenotype of leukemic T-cells, high CD5 expression by regulatory T-cells, CD5^lowphenotype of autoreactive T-cells, etc. A low CD5 expression triggers activation-induced cell death upon antigenic stimulation. There are three forms of CD5: membrane CD5 (mCD5), intracellular CD5 (cCD5) and soluble CD5 (sCD5). mCD5 and cCD5 are generated from conventional and non-conventional mRNA variants, i.e., E1A and E1B, respectively. E1B variant encoding cCD5 is derived from a human endogenous retrovirus segment inserted 8.2 kb upstream to conventional E1A exon. Various conditions, such as leukemia, exposure to hydrocarbon, hypoxia, etc., can trigger E1B transcription and, thus, cCD5 expression. Blocking mCD5 with mAb can restore immune response, effectively targeting cancer. Understanding cCD5, linked to leukemogenesis, can offer new avenues of immunotherapy.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"144 ","pages":"431-460"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466748","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":"Deciphering protein aggregation: Insights into morphology, contributing factors, and molecular pathologies.","authors":"Sree Hima, N Aiswarya, Chandran Remya, D M Vasudevan, K V Dileep, Dileep Francis","doi":"10.1016/bs.apcsb.2024.11.009","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.11.009","url":null,"abstract":"<p><p>Protein aggregation research stands at the cutting edge of biomedical science, offering crucial insights into the molecular underpinnings of neurodegenerative and amyloid-associated diseases. Significant advancements in deciphering the structural, biophysical, and molecular intricacies of protein misfolding are driving the development of innovative therapies. Emerging approaches, from small molecule inhibitors to sophisticated polymer-based therapeutics, hold great promise for alleviating the toxic impacts of aggregation with the potential to prevent, delay, or even reverse disease progression. Despite these advances, the field contends with substantial challenges. The polymorphic and complex nature of protein aggregates poses major obstacles to both research and therapeutic design. Yet, interdisciplinary methodologies-integrating advanced spectroscopic, imaging, and computational tools-are creating new pathways to address these complexities, effectively bridging molecular breakthroughs and practical therapeutic applications. The rapid shift of foundational discoveries to clinical trials marks a pivotal step forward, instilling new hope for patients with protein aggregation disorders. Each breakthrough propels us closer to life-changing therapies that may reshape the outlook for these patients. The promise of precise and effective treatments is driving a transformative shift in medical science, establishing protein aggregation research as a crucial pillar in combating these challenging diseases and offering a beacon of hope for the future of neurodegenerative care.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"145 ","pages":"23-71"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961773","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":"Monoclonal antibodies - A repertoire of therapeutics.","authors":"Suman Tapryal","doi":"10.1016/bs.apcsb.2024.11.001","DOIUrl":"10.1016/bs.apcsb.2024.11.001","url":null,"abstract":"<p><p>Antibodies are a class of biomolecules armed with extraordinary diversity, unmatched in the biological world by any other class of molecules. This characteristic feature equips antibodies to recognize, bind, and eliminate an infinite number of pathogens/antigens facilitated by their effector functions. The repertoire of natural binding specificities of antibodies (Abs) is greater than the calculated estimate of ∼10¹² in humans, as a naive, single antigen-binding site may bind more than one antigen employing the plasticity in antigen-antibody interactions, potentiating Abs to fight infinite pathogenic insults and restrict the development of cancers. Additionally, advanced technological interventions, by allowing manipulation of the germline and acquired specificities of human/animal immunoglobulins (Ig) have contributed immensely to broaden their existing repertoire and scope of clinical applications. The available natural repertoire of Ig and Ig-like molecules in other animals, e.g., mice, horses, cows, pigs, rabbits, camels, llamas, etc., further diversified the source of unique antigen-binding specificities. The recombinant DNA technology, in association with hybridoma , transgenic, and phage display technologies, has helped create a parallel repertoire of unique antibody molecules [animal Abs, camelid heavy chain Abs (hcAbs), chimeric Abs, chimeric hcAbs, humanized Abs, humanized nanobody (Nb)-hcAbs, human Abs, etc.], monoclonal Ab (mAb) derived fragments [antigen-binding-fragment (Fab), single-chain-variable-fragment (scFv), variable-fragement (Fv), single-variable-domain of hcAbs (V_HH), bispecific scFv, diabodies, triabodies, intrabodies, bispecific Fabs, tri-specific Fabs, etc.), and immunoconjugates generated by fusing/conjugating mAb fragments with enzyme, toxin, prodrug etc., molecules. The current chapter provides a detailed description of the natural and engineered antibody repertoires and discusses various strategies using which these molecules are being inducted as novel immunotherapeutics for treating a significant number of human diseases.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"144 ","pages":"151-212"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466650","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":"Exploring immunotherapy with antibody-drug conjugates in solid tumor oncology.","authors":"Takhellambam Malemnganba, Anurag Kumar Pandey, Amit Mishra, Sanjana Mehrotra, Vijay Kumar Prajapati","doi":"10.1016/bs.apcsb.2024.10.016","DOIUrl":"10.1016/bs.apcsb.2024.10.016","url":null,"abstract":"<p><p>Immunotherapy has emerged as a hallmark of hope in the formidable battle against solid tumors such as breast cancer, colorectal cancer, etc., with antibody-drug conjugates (ADCs) starting a new era of precision medicine. This chapter delves into the dynamic landscape of immunotherapeutic strategies, focusing on the transformative potential of ADCs. ADCs represent a combination of chemotherapy and immunotherapy, more innovative chemotherapy. We emphasize the intricate interplay between tumor biology and therapeutic intervention, uncovering the mechanisms underlying ADC efficacy and the hurdles they must overcome. Each facet of ADC development is carefully examined, from the delicate balance between payload potency and safety to the quest for enhanced tumor penetration. We also elucidate the synergistic potential of combining ADCs with existing modalities, including chemotherapy and radiation therapy, to amplify therapeutic outcomes while mitigating adverse effects. As we navigate the complexities of solid tumor oncology, a profound understanding of the immunotherapeutic potential of ADCs is gained, offering hope for a cure for patients and clinicians alike. Henceforth, we delve into this transformative journey as we advance in solid tumor treatment regimens using immunotherapy with ADCs, poised at the forefront of oncological innovation.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"144 ","pages":"259-286"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466729","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}