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CATH (https://www.cathdb.info) identifies domains in protein structures from wwPDB and classifies these into evolutionary superfamilies, thereby providing structural and functional annotations. There are two levels: CATH-B, a daily snapshot of the latest domain structures and superfamily assignments, and CATH+, with additional derived data, such as predicted sequence domains, and functionally coherent sequence subsets (Functional Families or FunFams). The latest CATH+ release, version 4.3, significantly increases coverage of structural and sequence data, with an addition of 65,351 fully-classified domains structures (+15%), providing 500 238 structural domains, and 151 million predicted sequence domains (+59%) assigned to 5481 superfamilies. The FunFam generation pipeline has been re-engineered to cope with the increased influx of data. Three times more sequences are captured in FunFams, with a concomitant increase in functional purity, information content and structural coverage. FunFam expansion increases the structural annotations provided for experimental GO terms (+59%). We also present CATH-FunVar web-pages displaying variations in protein sequences and their proximity to known or predicted functional sites. We present two case studies (1) putative cancer drivers and (2) SARS-CoV-2 proteins. Finally, we have improved links to and from CATH including SCOP, InterPro, Aquaria and 2DProt.
Assuntos
Biologia Computacional/estatística & dados numéricos , Bases de Dados de Proteínas/estatística & dados numéricos , Domínios Proteicos , Proteínas/química , Sequência de Aminoácidos , COVID-19/epidemiologia , COVID-19/prevenção & controle , COVID-19/virologia , Biologia Computacional/métodos , Epidemias , Humanos , Internet , Anotação de Sequência Molecular , Proteínas/genética , Proteínas/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Análise de Sequência de Proteína/métodos , Homologia de Sequência de Aminoácidos , Proteínas Virais/química , Proteínas Virais/genética , Proteínas Virais/metabolismoRESUMO
Alternative splicing can expand the diversity of proteomes. Homologous mutually exclusive exons (MXEs) originate from the same ancestral exon and result in polypeptides with similar structural properties but altered sequence. Why would some genes switch homologous exons and what are their biological impact? Here, we analyse the extent of sequence, structural and functional variability in MXEs and report the first large scale, structure-based analysis of the biological impact of MXE events from different genomes. MXE-specific residues tend to map to single domains, are highly enriched in surface exposed residues and cluster at or near protein functional sites. Thus, MXE events are likely to maintain the protein fold, but alter specificity and selectivity of protein function. This comprehensive resource of MXE events and their annotations is available at: http://gene3d.biochem.ucl.ac.uk/mxemod/. These findings highlight how small, but significant changes at critical positions on a protein surface are exploited in evolution to alter function.
Assuntos
Processamento Alternativo/genética , Éxons/genética , Genoma/genética , Proteínas , Animais , Evolução Molecular , Genômica , Humanos , Proteínas/genética , Proteínas/fisiologiaRESUMO
Genome3D (https://www.genome3d.eu) is a freely available resource that provides consensus structural annotations for representative protein sequences taken from a selection of model organisms. Since the last NAR update in 2015, the method of data submission has been overhauled, with annotations now being 'pushed' to the database via an API. As a result, contributing groups are now able to manage their own structural annotations, making the resource more flexible and maintainable. The new submission protocol brings a number of additional benefits including: providing instant validation of data and avoiding the requirement to synchronise releases between resources. It also makes it possible to implement the submission of these structural annotations as an automated part of existing internal workflows. In turn, these improvements facilitate Genome3D being opened up to new prediction algorithms and groups. For the latest release of Genome3D (v2.1), the underlying dataset of sequences used as prediction targets has been updated using the latest reference proteomes available in UniProtKB. A number of new reference proteomes have also been added of particular interest to the wider scientific community: cow, pig, wheat and mycobacterium tuberculosis. These additions, along with improvements to the underlying predictions from contributing resources, has ensured that the number of annotations in Genome3D has nearly doubled since the last NAR update article. The new API has also been used to facilitate the dissemination of Genome3D data into InterPro, thereby widening the visibility of both the annotation data and annotation algorithms.
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Proteínas/química , Bases de Dados de Proteínas , Proteínas/classificação , Proteínas/genética , Interface Usuário-ComputadorRESUMO
Gene3D (http://gene3d.biochem.ucl.ac.uk) is a database of globular domain annotations for millions of available protein sequences. Gene3D has previously featured in the Database issue of NAR and here we report a significant update to the Gene3D database. The current release, Gene3D v16, has significantly expanded its domain coverage over the previous version and now contains over 95 million domain assignments. We also report a new method for dealing with complex domain architectures that exist in Gene3D, arising from discontinuous domains. Amongst other updates, we have added visualization tools for exploring domain annotations in the context of other sequence features and in gene families. We also provide web-pages to visualize other domain families that co-occur with a given query domain family.
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Bases de Dados de Proteínas , Genoma , Domínios Proteicos , Proteínas/química , Software , Sequência de Aminoácidos , Animais , Gráficos por Computador , Humanos , Internet , Anotação de Sequência Molecular , Proteínas/genética , Proteínas/metabolismo , Análise de Sequência de ProteínaRESUMO
Gene3D http://gene3d.biochem.ucl.ac.uk is a database of domain annotations of Ensembl and UniProtKB protein sequences. Domains are predicted using a library of profile HMMs representing 2737 CATH superfamilies. Gene3D has previously featured in the Database issue of NAR and here we report updates to the website and database. The current Gene3D (v14) release has expanded its domain assignments to â¼ 20,000 cellular genomes and over 43 million unique protein sequences, more than doubling the number of protein sequences since our last publication. Amongst other updates, we have improved our Functional Family annotation method. We have also improved the quality and coverage of our 3D homology modelling pipeline of predicted CATH domains. Additionally, the structural models have been expanded to include an extra model organism (Drosophila melanogaster). We also document a number of additional visualization tools in the Gene3D website.
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Bases de Dados de Proteínas , Estrutura Terciária de Proteína , Humanos , Internet , Modelos Moleculares , Anotação de Sequência Molecular , Domínios e Motivos de Interação entre Proteínas , Estrutura Terciária de Proteína/genéticaRESUMO
The COVID-19 disease is an ongoing global health concern. Although vaccination provides some protection, people are still susceptible to re-infection. Ostensibly, certain populations or clinical groups may be more vulnerable. Factors causing these differences are unclear and whilst socioeconomic and cultural differences are likely to be important, human genetic factors could influence susceptibility. Experimental studies indicate SARS-CoV-2 uses innate immune suppression as a strategy to speed-up entry and replication into the host cell. Therefore, it is necessary to understand the impact of variants in immunity-associated human proteins on susceptibility to COVID-19. In this work, we analysed missense coding variants in several SARS-CoV-2 proteins and their human protein interactors that could enhance binding affinity to SARS-CoV-2. We curated a dataset of 19 SARS-CoV-2: human protein 3D-complexes, from the experimentally determined structures in the Protein Data Bank and models built using AlphaFold2-multimer, and analysed the impact of missense variants occurring in the protein-protein interface region. We analysed 468 missense variants from human proteins and 212 variants from SARS-CoV-2 proteins and computationally predicted their impacts on binding affinities for the human viral protein complexes. We predicted a total of 26 affinity-enhancing variants from 13 human proteins implicated in increased binding affinity to SARS-CoV-2. These include key-immunity associated genes (TOMM70, ISG15, IFIH1, IFIT2, RPS3, PALS1, NUP98, AXL, ARF6, TRIMM, TRIM25) as well as important spike receptors (KREMEN1, AXL and ACE2). We report both common (e.g., Y13N in IFIH1) and rare variants in these proteins and discuss their likely structural and functional impact, using information on known and predicted functional sites. Potential mechanisms associated with immune suppression implicated by these variants are discussed. Occurrence of certain predicted affinity-enhancing variants should be monitored as they could lead to increased susceptibility and reduced immune response to SARS-CoV-2 infection in individuals/populations carrying them. Our analyses aid in understanding the potential impact of genetic variation in immunity-associated proteins on COVID-19 susceptibility and help guide drug-repurposing strategies.
Assuntos
COVID-19 , Mutação de Sentido Incorreto , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , SARS-CoV-2/imunologia , COVID-19/genética , COVID-19/virologia , COVID-19/imunologia , Reposicionamento de Medicamentos , Proteínas Virais/genética , Proteínas Virais/metabolismo , Ligação Proteica , Predisposição Genética para Doença , Suscetibilidade a Doenças , Tratamento Farmacológico da COVID-19RESUMO
Cancer remains a global problem, with millions of new cases diagnosed yearly and countless lives lost. The financial burden of cancer therapy, along with worries about the long-term safety of existing medicines, necessitates the investigation of alternative approaches to cancer prevention. Probiotics generate chemopreventive compounds such as bacteriocins, short-chain fatty acids (SCFA), and extracellular polymeric substances (EPS), which have demonstrated the ability to impede cancer cell proliferation, induce apoptosis, and bolster the expression of pro-apoptotic genes. On the other hand, prebiotics, classified as non-digestible food ingredients, promote the proliferation of probiotics within the colon, thereby ensuring sustained functionality of the gut microbiota. Consequently, the synergistic effect of combining prebiotics with probiotics, known as the synbiotic effect, in dietary interventions holds promise for potentially mitigating cancer risk and augmenting preventive measures. The utilization of gut microbiota in cancer treatment has shown promise in alleviating adverse health effects. This review explored the potential and the role of probiotics and synbiotics in enhancing health and contributing to cancer prevention efforts. In this review, the applications of functional probiotics and synbiotics, the mechanisms of action of probiotics in cancer, and the relationship of probiotics with various drugs were discussed, shedding light on the potential of probiotics and synbiotics to alleviate the burdens of cancer treatment.
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Proteins provide the basis for cellular function. Having multiple versions of the same protein within a single organism provides a way of regulating its activity or developing novel functions. Post-translational modifications of proteins, by means of adding/removing chemical groups to amino acids, allow for a well-regulated and controlled way of generating functionally distinct protein species. Alternative splicing is another method with which organisms possibly generate new isoforms. Additionally, gene duplication events throughout evolution generate multiple paralogs of the same genes, resulting in multiple versions of the same protein within an organism. In this review, we discuss recent advancements in the study of these three methods of protein diversification and provide illustrative examples of how they affect protein structure and function.
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Processamento Alternativo , Duplicação Gênica , Evolução Molecular , Isoformas de Proteínas/genética , Processamento de Proteína Pós-TraducionalRESUMO
Antimicrobial peptides (AMPs) are short peptides with a broad spectrum of antimicrobial activity. They play a key role in the host innate immunity of many organisms. The growing threat of microorganisms resistant to antimicrobial agents and the lack of new commercially available antibiotics have made in silico discovery of AMPs increasingly important. Machine learning (ML) has improved the speed and efficiency of AMP discovery while reducing the cost of experimental approaches. Despite various ML platforms developed, there is still a lack of integrative use of ML platforms for AMP discovery from publicly available protein databases. Therefore, our study aims to screen potential AMPs with antibiofilm properties from databases using ML platforms, followed by protein-peptide molecular docking analysis and molecular dynamics (MD) simulations. A total of 5850 peptides classified as non-AMP were screened from UniProtKB and analyzed using various online ML platforms (e.g., CAMPr3, DBAASP, dPABBs, Hemopred, and ToxinPred). Eight potential AMP peptides against Klebsiella pneumoniae with antibiofilm, non-toxic and non-hemolytic properties were then docked to MrkH, a transcriptional regulator of type 3 fimbriae involved in biofilm formation. Five of eight peptides bound more strongly than the native MrkH ligand when analyzed using HADDOCK and HPEPDOCK. Following the docking studies, our MD simulated that a Neuropeptide B (Peptide 3) bind strongly to the MrkH active sites. The discovery of putative AMPs that exceed the binding energies of the native ligand underscores the utility of the combined ML and molecular simulation strategies for discovering novel AMPs with antibiofilm properties.
Assuntos
Peptídeos Antimicrobianos , Klebsiella pneumoniae , Aprendizado de Máquina , Antibacterianos/farmacologia , Antibacterianos/metabolismo , Peptídeos Antimicrobianos/farmacologia , Klebsiella pneumoniae/efeitos dos fármacos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica MolecularRESUMO
Curcumin, one of the major ingredients of turmeric (Curcuma longa), has been widely reported for its diverse bioactivities, including against malaria and inflammatory-related diseases. However, curcumin's low bioavailability limits its potential as an antimalarial and anti-inflammatory agent. Therefore, research on the design and synthesis of novel curcumin derivatives is being actively pursued to improve the pharmacokinetic profile and efficacy of curcumin. This review discusses the antimalarial and anti-inflammatory activities and the structure-activity relationship (SAR), as well as the mechanisms of action of curcumin and its derivatives in malarial treatment. This review provides information on the identification of the methoxy phenyl group responsible for the antimalarial activity and the potential sites and functional groups of curcumin for structural modification to improve its antimalarial and anti-inflammatory actions, as well as potential molecular targets of curcumin derivatives in the context of malaria and inflammation.
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Deep-learning (DL) methods like DeepMind's AlphaFold2 (AF2) have led to substantial improvements in protein structure prediction. We analyse confident AF2 models from 21 model organisms using a new classification protocol (CATH-Assign) which exploits novel DL methods for structural comparison and classification. Of ~370,000 confident models, 92% can be assigned to 3253 superfamilies in our CATH domain superfamily classification. The remaining cluster into 2367 putative novel superfamilies. Detailed manual analysis on 618 of these, having at least one human relative, reveal extremely remote homologies and further unusual features. Only 25 novel superfamilies could be confirmed. Although most models map to existing superfamilies, AF2 domains expand CATH by 67% and increases the number of unique 'global' folds by 36% and will provide valuable insights on structure function relationships. CATH-Assign will harness the huge expansion in structural data provided by DeepMind to rationalise evolutionary changes driving functional divergence.
Assuntos
Furilfuramida , Proteínas , Humanos , Bases de Dados de Proteínas , Proteínas/químicaRESUMO
Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is an ongoing pandemic that causes significant health/socioeconomic burden. Variants of concern (VOCs) have emerged affecting transmissibility, disease severity and re-infection risk. Studies suggest that the - N-terminal domain (NTD) of the spike protein may have a role in facilitating virus entry via sialic-acid receptor binding. Furthermore, most VOCs include novel NTD variants. Despite global sequence and structure similarity, most sialic-acid binding pockets in NTD vary across coronaviruses. Our work suggests ongoing evolutionary tuning of the sugar-binding pockets and recent analyses have shown that NTD insertions in VOCs tend to lie close to loops. We extended the structural characterisation of these sugar-binding pockets and explored whether variants could enhance sialic acid-binding. We found that recent NTD insertions in VOCs (i.e., Gamma, Delta and Omicron variants) and emerging variants of interest (VOIs) (i.e., Iota, Lambda and Theta variants) frequently lie close to sugar-binding pockets. For some variants, including the recent Omicron VOC, we find increases in predicted sialic acid-binding energy, compared to the original SARS-CoV-2, which may contribute to increased transmission. These binding observations are supported by molecular dynamics simulations (MD). We examined the similarity of NTD across Betacoronaviruses to determine whether the sugar-binding pockets are sufficiently similar to be exploited in drug design. Whilst most pockets are too structurally variable, we detected a previously unknown highly structurally conserved pocket which can be investigated in pursuit of a generic pan-Betacoronavirus drug. Our structure-based analyses help rationalise the effects of VOCs and provide hypotheses for experiments. Our findings suggest a strong need for experimental monitoring of changes in NTD of VOCs.
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Several species in Brassicaceae produce glucosinolates (GSLs) to protect themselves against pests. As demonstrated in A. thaliana, the reallocation of defence compounds, of which GSLs are a major part, is highly dependent on transport processes and serves to protect high-value tissues such as reproductive tissues. This study aimed to identify potential GSL-transporter proteins (TPs) using a network-biology approach. The known A. thaliana GSL genes were retrieved from the literature and pathway databases and searched against several co-expression databases to generate a gene network consisting of 1267 nodes and 14,308 edges. In addition, 1151 co-expressed genes were annotated, integrated, and visualised using relevant bioinformatic tools. Based on three criteria, 21 potential GSL genes encoding TPs were selected. The AST68 and ABCG40 potential GSL TPs were chosen for further investigation because their subcellular localisation is similar to that of known GSL TPs (SULTR1;1 and SULTR1;2) and ABCG36, respectively. However, AST68 was selected for a molecular-docking analysis using AutoDOCK Vina and AutoDOCK 4.2 with the generated 3D model, showing that both domains were well superimposed on the homologs. Both molecular-docking tools calculated good binding-energy values between the sulphate ion and Ser419 and Val172, with the formation of hydrogen bonds and van der Waals interactions, respectively, suggesting that AST68 was one of the sulphate transporters involved in GSL biosynthesis. This finding illustrates the ability to use computational analysis on gene co-expression data to screen and characterise plant TPs on a large scale to comprehensively elucidate GSL metabolism in A. thaliana. Most importantly, newly identified potential GSL transporters can serve as molecular tools in improving the nutritional value of crops.
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Draft genome sequences were obtained for four methicillin-resistant Staphylococcus aureus (MRSA) strains isolated from various wards of the Hospital Canselor Tuanku Muhriz (HCTM), Kuala Lumpur, Malaysia, in 2017. Using different bioinformatics tools, we annotated the draft genomes and identified multiple antimicrobial resistance genes.
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SARS-CoV-2, the causative agent of the COVID-19 pandemic, can infect a wide range of mammals. Since its spread in humans, secondary host jumps of SARS-CoV-2 from humans to multiple domestic and wild populations of mammals have been documented. Understanding the extent of adaptation to these animal hosts is critical for assessing the threat that the spillback of animal-adapted SARS-CoV-2 into humans poses. We compare the genomic landscapes of SARS-CoV-2 isolated from animal species to that in humans, profiling the mutational biases indicative of potentially different selective pressures in animals. We focus on viral genomes isolated from mink (Neovison vison) and white-tailed deer (Odocoileus virginianus) for which multiple independent outbreaks driven by onward animal-to-animal transmission have been reported. We identify five candidate mutations for animal-specific adaptation in mink (NSP9_G37E, Spike_F486L, Spike_N501T, Spike_Y453F, ORF3a_L219V), and one in deer (NSP3a_L1035F), though they appear to confer a minimal advantage for human-to-human transmission. No considerable changes to the mutation rate or evolutionary trajectory of SARS-CoV-2 has resulted from circulation in mink and deer thus far. Our findings suggest that minimal adaptation was required for onward transmission in mink and deer following human-to-animal spillover, highlighting the 'generalist' nature of SARS-CoV-2 as a mammalian pathogen.
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COVID-19 , Cervos , Animais , COVID-19/genética , Adaptação ao Hospedeiro , Humanos , Pandemias , SARS-CoV-2/genéticaRESUMO
Coronavirus-like organisms have been previously identified in Arthropod ectoparasites (such as ticks and unfed cat flea). Yet, the question regarding the possible role of these arthropods as SARS-CoV-2 passive/biological transmission vectors is still poorly explored. In this study, we performed in silico structural and binding energy calculations to assess the risks associated with possible ectoparasite transmission. We found sufficient similarity between ectoparasite ACE and human ACE2 protein sequences to build good quality 3D-models of the SARS-CoV-2 Spike:ACE complex to assess the impacts of ectoparasite mutations on complex stability. For several species (e.g., water flea, deer tick, body louse), our analyses showed no significant destabilisation of the SARS-CoV-2 Spike:ACE complex, suggesting these species would bind the viral Spike protein. Our structural analyses also provide structural rationale for interactions between the viral Spike and the ectoparasite ACE proteins. Although we do not have experimental evidence of infection in these ectoparasites, the predicted stability of the complex suggests this is possible, raising concerns of a possible role in passive transmission of the virus to their human hosts.
Assuntos
Proteínas de Artrópodes/metabolismo , Artrópodes/metabolismo , Peptidil Dipeptidase A/metabolismo , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Proteínas de Artrópodes/química , Proteínas de Artrópodes/genética , Artrópodes/química , Artrópodes/classificação , Artrópodes/genética , Sítios de Ligação , COVID-19/transmissão , Ectoparasitoses/parasitologia , Humanos , Modelos Moleculares , Mutação , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/genética , Filogenia , Ligação Proteica , SARS-CoV-2/química , SARS-CoV-2/genética , Homologia de Sequência , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismoRESUMO
Salinisation of soil is associated with urban pollution, industrial development and rising sea level. Understanding how high salinity is managed at the plant cellular level is vital to increase sustainable farming output. Previous studies focus on plant stress responses under salinity tolerance. Yet, there is limited knowledge about the mechanisms involved from stress state until the recovery state; our research aims to close this gap. By using the most tolerance genotype (SS1-14) and the most susceptible genotype (SS2-18), comparative physiological, metabolome and post-harvest assessments were performed to identify the underlying mechanisms for salinity stress recovery in plant cells. The up-regulation of glutamine, asparagine and malonic acid were found in recovered-tolerant genotype, suggesting a role in the regulation of panicle branching and spikelet formation for survival. Rice could survive up to 150 mM NaCl (â¼15 ds/m) with declined of production rate 5-20% ranged from tolerance to susceptible genotype. This show that rice farming may still be viable on the high saline affected area with the right selection of salt-tolerant species, including glycophytes. The salt recovery biomarkers identified in this study and the adaption underlined could be empowered to address salinity problem in rice field.
Assuntos
Oryza , Genótipo , Metabolômica , Oryza/genética , Salinidade , Tolerância ao Sal , Estresse FisiológicoRESUMO
The red palm weevil (RPW; Rhynchophorus ferrugineus Olivier (Coleoptera Curculionidae)) is an invasive insect pest that is difficult to manage due to its nature of infesting the host palm trees from within. A holistic, molecular-based approach to identify proteins that correlate with RPW infestation could give useful insights into the vital processes that are prevalent to the host's infestation response and identify the potential biomarkers for an early detection technique. Here, a shotgun proteomic analysis was performed on oil palm (Elaeis guineensis; OP) under untreated (control), wounding by drilling (wounded), and artificial larval infestation (infested) conditions at three different time points to characterise the RPW infestation response at three different stages. KEGG pathway enrichment analysis revealed many overlapping pathways between the control, wounded, and infested groups. Further analysis via literature searches narrowed down biologically relevant proteins into categories, which were photosynthesis, growth, and stress response. Overall, the patterns of protein expression suggested abscisic acid (ABA) hormone signalling to be the primary driver of insect herbivory response. Interspecies molecular docking analysis between RPW ligands and OP receptor proteins provided putative interactions that result in ABA signalling activation. Seven proteins were selected as candidate biomarkers for early infestation detection based on their relevance and association with ABA signalling. The MS data are available via ProteomeXchange with identifier PXD028986. This study provided a deeper insight into the mechanism of stress response in OP in order to develop a novel detection method or improve crop management.
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In agriculture, the convenience and efficacy of chemical pesticides have become inevitable to manage cultivated crop production. Here, we review the worldwide use of pesticides based on their categories, mode of actions and toxicity. Excessive use of pesticides may lead to hazardous pesticide residues in crops, causing adverse effects on human health and the environment. A wide range of high-tech-analytical methods are available to analyse pesticide residues. However, they are mostly time-consuming and inconvenient for on-site detection, calling for the development of biosensors that detect cellular changes in crops. Such new detection methods that combine biological and physicochemical knowledge may overcome the shortage in current farming to develop sustainable systems that support environmental and human health. This review also comprehensively compiles domestic pesticide residues removal tips from vegetables and fruits. Synthetic pesticide alternatives such as biopesticide and nanopesticide are greener to the environment. However, its safety assessment for large-scale application needs careful evaluation. Lastly, we strongly call for reversions of pesticide application trends based on the changing climate, which is lacking in the current scenario.