Unlocking the Secrets of NSP3: AlphaFold2-assisted Domain Determination in SARS-CoV-2 Protein

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 15, 2025

Abstract Non-structural protein 3 (nsp3) is crucial for the SARS-CoV-2 infection cycle. It largest of virus, consisting roughly 2000 residues, and a major drug target. However, due to its size, disordered regions, transmembrane domains, atomic structure whole has not yet been established. Only 10 out 16 domains were individually determined in experiments. Here, we demonstrate how structural bioinformatics, AI-based fold prediction, traditional experiments complement each other can shed light on makeup this important protein, both related viruses. Our method be generalized multi-domain proteins, so describe it detail. prediction-based approach reveals previously undescribed folded domain, which could confirm experimentally. research also suggests potential function nidovirus-wide conserved domain Y1: This may involved assembly nsp3, nsp4, nsp6 into hexameric pore, was discovered by electron tomography exports RNA cytosol. The Y1-hexamer, however, expressed purified own. We provide revised segmentation nomenclature nsp3 based compilation previous our own findings.

Язык: Английский

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Twenty years in metalloprotein bioinformatics: A short history of a long journey

Journal of Inorganic Biochemistry, Год журнала: 2025, Номер 266, С. 112854 - 112854

Опубликована: Фев. 11, 2025

Язык: Английский

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Metal-coding assisted serological multi-omics profiling deciphers the role of selenium in COVID-19 immunity

Chemical Science, Год журнала: 2023, Номер 14(38), С. 10570 - 10579

Опубликована: Янв. 1, 2023

Uncovering how host metal(loid)s mediate the immune response against invading pathogens is critical for better understanding pathogenesis mechanism of infectious disease. Clinical data show that imbalance closely associated with severity and mortality COVID-19. However, it remains elusive metal(loid)s, which are essential elements all forms life multiple diseases if dysregulated, involved in COVID-19 pathophysiology immunopathology. Herein, we built up a metal-coding assisted multiplexed serological metallome immunoproteome profiling system to characterize links immunity. We found distinct features patients compared non-infected control subjects, may serve as biomarker disease diagnosis. Moreover, generated first correlation network between immunity mediators, unbiasedly uncovered strong association selenium interleukin-10 (IL-10). Supplementation cells resulted enhanced IL-10 expression B reduced induction proinflammatory cytokines CD4+ T cells. The selenium-enhanced production was confirmed be attributable activation ERK Akt pathways. further validated our cellular SARS-CoV-2-infected K18-hACE2 mice, supplementation alleviated SARS-CoV-2-induced lung damage characterized by decreased alveolar inflammatory infiltrates through restoration virus-repressed selenoproteins alleviate oxidative stress. Our approach can readily extended other understand defends regulation metallome.

Язык: Английский

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Long-Term Effects of SARS-CoV-2 Infection on Metal Homeostasis

Journal of Trace Elements in Medicine and Biology, Год журнала: 2025, Номер 88, С. 127625 - 127625

Опубликована: Фев. 27, 2025

Язык: Английский

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Structural Bioinformatics and Deep Learning of Metalloproteins: Recent Advances and Applications

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(14), С. 7684 - 7684

Опубликована: Июль 12, 2022

All living organisms require metal ions for their energy production and metabolic biosynthetic processes. Within cells, the involved in formation of adducts interact with metabolites macromolecules (proteins nucleic acids). The proteins that binding to one or more order be able carry out physiological function are called metalloproteins. About third all protein structures Protein Data Bank involve Over past few years there has been tremendous progress number computational tools techniques making use 3D structural information support investigation This trend boosted by successful applications neural networks machine/deep learning approaches molecular biology at large. In this review, we discuss recent advances development availability resources dealing metalloproteins from a structure-based perspective. We start addressing prediction metal-binding sites (MBSs) using on apo-proteins. Then, provide an overview methods lessons learned comparison MBSs fold-independent manner. then move describing databases metalloprotein/MBS structures. Finally, summarizing ML/DL enhancing functional interpretation metalloprotein

Язык: Английский

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Mechanistic Insights into Targeting SARS-CoV-2 Papain-like Protease in the Evolution and Management of COVID-19

BioChem, Год журнала: 2024, Номер 4(3), С. 268 - 299

Опубликована: Сен. 23, 2024

The COVID-19 pandemic, instigated by the emergence of novel coronavirus, SARS-CoV-2, created an incomparable global health crisis. Due to its highly virulent nature, identifying potential therapeutic agents against this lethal virus is crucial. PLpro a key protein involved in viral polyprotein processing and immune system evasion, making it prime target for development antiviral drugs combat COVID-19. To expedite search candidates, review delved into computational studies. Recent investigations have harnessed methods identify promising inhibitors targeting PLpro, aiming suppress activity. Molecular docking techniques were employed researchers explore binding sites within catalytic region PLpro. elucidates functional structural properties SARS-CoV-2 underscoring significance pathogenicity replication. Through comprehensive all-atom molecular dynamics (MD) simulations, stability drug–PLpro complexes was assessed, providing dynamic insights their interactions. By evaluating energy estimates from MD stable with identified. This offers overview drug/lead candidates discovered thus far using diverse silico methodologies, encompassing drug repurposing, structure-based, ligand-based virtual screenings. Additionally, identified are listed based on chemical structures meticulously examined according various parameters, such as estimated free (ΔG), types intermolecular interactions, PLpro–ligand complexes, determined outcomes simulations. Underscoring pivotal role battle COVID-19, establishes robust foundation integrating modeling, insights. continual imperative improvement existing exploring compounds remains paramount efforts evolution management hinge symbiotic relationship between experimental validation, interdisciplinary synergy crucial endeavor.

Язык: Английский

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The putative metal-binding proteome of the Coronaviridae family

Metallomics, Год журнала: 2023, Номер 15(1)

Опубликована: Янв. 1, 2023

Abstract Metalloproteins are well-known for playing various physicochemical processes in all life forms, including viruses. Some life-threatening viruses (such as some members of the Coronaviridae family viruses) emerged and remerged frequently rapidly transmitted throughout globe. This study aims to identify characterize metal-binding proteins (MBPs) further provides insight into MBP’s role sustaining propagating inside a host cell outer environment. In this study, available proteome was exploited. Identified potential MBPs were analyzed their functional domains, structural aspects, subcellular localization. We also demonstrate phylogenetic aspects predicted among other understand evolutionary trend respective hosts. A total 256 from 51 different species coronaviruses MBPs. These perform key roles replication survival within cell. Cysteine, aspartic acid, threonine, glutamine amino acid residues interacting with metal ions. Our observations indicate that metalloproteins circulated evolved hosts, which supports zoonotic nature coronaviruses. The comprehensive information on may be helpful designing novel therapeutic metalloprotein targets. Moreover, viral can help virus pathogenesis virus–host interactions.

Язык: Английский

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Boosting immunity: synergistic antiviral effects of luteolin, vitamin C, magnesium and zinc against SARS-CoV-2 3CLpro

Bioscience Reports, Год журнала: 2024, Номер 44(8)

Опубликована: Июль 24, 2024

SARS-CoV-2 was first discovered in 2019 and has disseminated throughout the globe to pandemic levels, imposing significant health economic burdens. Although vaccines against have been developed, their long-term efficacy specificity not determined, antiviral drugs remain necessary. Flavonoids, which are commonly found plants, fruits, vegetables part of human diet, attracted considerable attention as potential therapeutic agents due antimicrobial activities effects on other biological activities, such inflammation. The present study uses a combination biochemical, cellular, molecular dynamics, docking experiments provide compelling evidence that flavonoid luteolin (2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4H-chromen-4-one) activity 3-chymotrypsin-like protease (3CLpro) is synergistically enhanced by magnesium, zinc, vitamin C. IC50 2 µM 3CLpro 78 decreases 10-fold 7.6 presence Thermodynamic stability analyses revealed minimal structure 3CLpro, whereas metal ions C significantly alter thermodynamic protease. Interactome analysis uncovered host-virus interactions functional clusters associated with activity, supporting relevance this flavone for combating infection. This comprehensive investigation sheds light luteolin's provides insights into its mechanisms action SARS-CoV-2. novel formulation luteolin, may be an effective avenue treating COVID-19 patients.

Язык: Английский

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Direct causal variable discovery leveraging the invariance principle: application in biomedical studies

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 29, 2024

Abstract Accurate identification of direct causal(parental) variables for a target is primary interest in many applications, especially biomedicine. It could promote our understanding the underlying pathophysiological mechanism and facilitate discovery new biomarkers therapeutic targets studied clinical outcomes. However, researchers are inclined to resort association-based machine learning methods identify outcome-associated variables. And identified may prove be irrelevant. On other hand, there lack an efficient method reliable parental set identification, high-dimensional settings (e.g., biomedicine). Here, we proposed novel two-stage approach (I-GCM) discover causal (including genetic variables) various Variable selection was first performed by PC-simple algorithm. Then it exploited invariance relations different (experimental) settings, which represented generalized covariance measure calculated from gradient-boosted trees, variable discovery. We verified through extensive simulations. This constantly yielded high precision (a.k.a., positive predictive value) specificity while maintaining satisfactory sensitivity general, consistently outperformed standard Notably, larger than 90% simulated scenarios, even settings. then applied 4 traits uncover corresponding Encouragingly, variables, genes pathways were supported literature. Our achieved superior performance identifying actual making particularly useful selecting what (genetic/clinical) risk factors follow up. Importantly, work represents one applications principle inference biomedical or studies, suggests avenue these

Язык: Английский

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Metalloproteome of human-infective RNA viruses: a study towards understanding the role of metal ions in virology

Pathogens and Disease, Год журнала: 2023, Номер 81

Опубликована: Янв. 1, 2023

Metalloproteins and metal-based inhibitors have been shown to effectively combat infectious diseases, particularly those caused by RNA viruses. In this study, a diverse set of bioinformatics methods was employed identify metal-binding proteins human Seventy-three viral with high probability being were identified. These included 40 zinc-, 47 magnesium- 14 manganese-binding belonging 29 species eight significant families, including Coronaviridae, Flaviviridae Retroviridae. Further functional characterization has revealed that these play critical role in several processes, replication, fusion host entry. They fall under the essential categories proteins, polymerase protease enzymes. Magnesium ion is abundantly predicted interact enzymes, followed zinc. addition, study also examined evolutionary aspects metalloproteins, offering insights into metal utilization patterns among different species. The analysis indicates are conserved within classes proteins. conclusion, findings provide knowledge on metalloproteins can serve as valuable foundation for future research area.

Язык: Английский

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