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1.
Frontiers of Medicine ; (4): 507-527, 2021.
Article in English | WPRIM | ID: wpr-888744

ABSTRACT

The avian influenza A (H7N9) virus is a zoonotic virus that is closely associated with live poultry markets. It has caused infections in humans in China since 2013. Five waves of the H7N9 influenza epidemic occurred in China between March 2013 and September 2017. H7N9 with low-pathogenicity dominated in the first four waves, whereas highly pathogenic H7N9 influenza emerged in poultry and spread to humans during the fifth wave, causing wide concern. Specialists and officials from China and other countries responded quickly, controlled the epidemic well thus far, and characterized the virus by using new technologies and surveillance tools that were made possible by their preparedness efforts. Here, we review the characteristics of the H7N9 viruses that were identified while controlling the spread of the disease. It was summarized and discussed from the perspectives of molecular epidemiology, clinical features, virulence and pathogenesis, receptor binding, T-cell responses, monoclonal antibody development, vaccine development, and disease burden. These data provide tools for minimizing the future threat of H7N9 and other emerging and re-emerging viruses, such as SARS-CoV-2.


Subject(s)
Animals , COVID-19 , China/epidemiology , Humans , Influenza A Virus, H7N9 Subtype , Influenza in Birds/epidemiology , Influenza, Human/prevention & control , Poultry , SARS-CoV-2
2.
Chinese Journal of Biotechnology ; (12): 1226-1233, 2018.
Article in Chinese | WPRIM | ID: wpr-687694

ABSTRACT

Overuse of antibiotics in livestock farming has enriched antibiotic-resistant genes as well as resistant bacteria in farm animals and their related environments. These antibiotic-resistant genes can spread to the natural environments by horizontal gene transfer and even to the food chain, posing a serious threat to the ecological environment, food safety and human health. With the development of genomic technology, the diversity and ecological distribution of antibiotic-resistant genes in farm animals and their related environments have been recently revealed. Here we summarized the research progress on antibiotic resistance genes in related fields, potential influence on human health, and future research needs.

3.
Protein & Cell ; (12): 866-877, 2016.
Article in English | WPRIM | ID: wpr-757362

ABSTRACT

Antibody-based PD-1/PD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre-existing T-cell function to modulate antitumor immunity. In this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-1/PD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural information will benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.


Subject(s)
Antibodies, Monoclonal , Allergy and Immunology , Therapeutic Uses , Antibodies, Monoclonal, Humanized , Allergy and Immunology , Therapeutic Uses , B7-H1 Antigen , Allergy and Immunology , Humans , Neoplasms , Drug Therapy , Allergy and Immunology , Pathology , Programmed Cell Death 1 Receptor , Allergy and Immunology , Signal Transduction , Allergy and Immunology , T-Lymphocytes , Allergy and Immunology
4.
Protein & Cell ; (12): 317-327, 2014.
Article in English | WPRIM | ID: wpr-757497

ABSTRACT

Cytotoxic T cells (CTLs) play a key role in the control of Hepatitis B virus (HBV) infection and viral clearance. However, most of identified CTL epitopes are derived from HBV of genotypes A and D, and few have been defined in virus of genotypes B and C which are more prevalent in Asia. As HBV core protein (HBc) is the most conservative and immunogenic component, in this study we used an overlapping 9-mer peptide pool covering HBc to screen and identify specific CTL epitopes. An unconventional HLA-A2-restricted epitope HBc141-149 was discovered and structurally characterized by crystallization analysis. The immunogenicity and anti-HBV activity were further determined in HBV and HLA-A2 transgenic mice. Finally, we show that mutations in HBc141-149 epitope are associated with viral parameters and disease progression in HBV infected patients. Our data therefore provide insights into the structure characteristics of this unconventional epitope binding to MHC-I molecules, as well as epitope specific CTL activity that orchestrate T cell response and immune evasion in HBV infected patients.


Subject(s)
Adult , Amino Acid Sequence , Animals , Binding Sites , Epitopes , Chemistry , Allergy and Immunology , Metabolism , Female , Genotype , HEK293 Cells , HLA-A2 Antigen , Metabolism , Hepatitis B Core Antigens , Chemistry , Allergy and Immunology , Metabolism , Hepatitis B virus , Genetics , Metabolism , Humans , Hydrogen Bonding , Male , Mice , Mice, Inbred BALB C , Mice, Transgenic , Middle Aged , Molecular Dynamics Simulation , Mutation , Protein Binding , Protein Structure, Tertiary , T-Lymphocytes, Cytotoxic , Allergy and Immunology , Metabolism
5.
Protein & Cell ; (12): 348-356, 2014.
Article in English | WPRIM | ID: wpr-757487

ABSTRACT

During virus infection, viral RNAs and mRNAs function as blueprints for viral protein synthesis and possibly as pathogen-associated molecular patterns (PAMPs) in innate immunity. Here, considering recent research progress in microRNAs (miRNAs) and competitive endogenous RNAs (ceRNAs), we speculate that viral RNAs act as sponges and can sequester endogenous miRNAs within infected cells, thus cross-regulating the stability and translational efficiency of host mRNAs with shared miRNA response elements. This cross-talk and these reciprocal interactions between viral RNAs and host mRNAs are termed "competitive viral and host RNAs" (cvhRNAs). We further provide recent experimental evidence for the existence of cvhRNAs networks in hepatitis B virus (HBV), as well as Herpesvirus saimiri (HVS), lytic murine cytomegalovirus (MCMV) and human cytomegalovirus (HCMV) infections. In addition, the cvhRNA hypothesis also predicts possible cross-regulation between host and other viruses, such as hepatitis C virus (HCV), HIV, influenza virus, human papillomaviruses (HPV). Since the interaction between miRNAs and viral RNAs also inevitably leads to repression of viral RNA function, we speculate that virus may evolve either to employ cvhRNA networks or to avoid miRNA targeting for optimal fitness within the host. CvhRNA networks may therefore play a fundamental role in the regulation of viral replication, infection establishment, and viral pathogenesis.


Subject(s)
Animals , DNA Viruses , Genetics , Physiology , Host-Pathogen Interactions , Physiology , Humans , MicroRNAs , Metabolism , RNA Viruses , Genetics , Physiology , RNA, Messenger , Metabolism , RNA, Viral , Metabolism , Virus Diseases , Allergy and Immunology , Virology , Virus Replication
6.
Protein & Cell ; (12): 603-615, 2014.
Article in English | WPRIM | ID: wpr-757472

ABSTRACT

The characterization of the human T-cell receptor (TCR) repertoire has made remarkable progress, with most of the work focusing on the TCRβ chains. Here, we analyzed the diversity and complexity of both the TCRα and TCRβ repertoires of three healthy donors. We found that the diversity of the TCRα repertoire is higher than that of the TCRβ repertoire, whereas the usages of the V and J genes tended to be preferential with similar TRAV and TRAJ patterns in all three donors. The V-J pairings, like the V and J gene usages, were slightly preferential. We also found that the TRDV1 gene rearranges with the majority of TRAJ genes, suggesting that TRDV1 is a shared TRAV/DV gene (TRAV42/DV1). Moreover, we uncovered the presence of tandem TRBD (TRB D gene) usage in ~2% of the productive human TCRβ CDR3 sequences.


Subject(s)
Complementarity Determining Regions , Genetics , DNA Primers , Chemistry , Genetics , Female , Gene Rearrangement, beta-Chain T-Cell Antigen Receptor , Genetics , Gene Rearrangement, delta-Chain T-Cell Antigen Receptor , Genetics , Genes, T-Cell Receptor beta , Genetics , Genetic Variation , High-Throughput Nucleotide Sequencing , Humans , Immunoglobulin Joining Region , Genetics , Immunoglobulin Variable Region , Genetics , Male , Receptors, Antigen, T-Cell, alpha-beta , Genetics
7.
Protein & Cell ; (12): 761-769, 2014.
Article in English | WPRIM | ID: wpr-757468

ABSTRACT

Bacterial cell division is strictly regulated in the formation of equal daughter cells. This process is governed by a series of spatial and temporal regulators, and several new factors of interest to the field have recently been identified. Here, we report the requirement of gluconate 5-dehydrogenase (Ga5DH) in cell division of the zoonotic pathogen Streptococcus suis. Ga5DH catalyzes the reversible reduction of 5-ketogluconate to D-gluconate and was localized to the site of cell division. The deletion of Ga5DH in S. suis resulted in a plump morphology with aberrant septa joining the progeny. A significant increase was also observed in cell length. These defects were determined to be the consequence of Ga5DH deprivation in S. suis causing FtsZ delocalization. In addition, the interaction of FtsZ with Ga5DH in vitro was confirmed by protein interaction assays. These results indicate that Ga5DH may function to prevent the formation of ectopic Z rings during S. suis cell division.


Subject(s)
Bacterial Proteins , Chemistry , Genetics , Metabolism , Cell Division , Cell Shape , Cytoskeletal Proteins , Chemistry , Genetics , Metabolism , Mutation , Oxidoreductases , Genetics , Metabolism , Protein Binding , Streptococcus suis
8.
Article in Chinese | WPRIM | ID: wpr-233275

ABSTRACT

Measles virus is an enveloped virus with a non-segmented negative-sense RNA genome. Two envelope glycoproteins on the viral surface, namely hemagglutinin (H) and membrane fusion protein (F), are responsible for the virus entry into susceptible host cells. The specific interaction between H and its cellular receptors is a key step in successful virus infection, determining the infectivity and tissue tropism of the measles virus. Thus far, three H receptors have been identified, including the complement regulatory molecule CD46, the signaling lymphocyte activation molecule (SLAM) and the cell adhesion molecule Nectin-4. Here, we reviewed our molecular understanding on the recognition mechanism of these receptors by the viral H protein, aiming to promote future studies on antiviral drug design and measles virus-based oncolytic therapy.


Subject(s)
Animals , Antigens, CD , Metabolism , Cell Adhesion Molecules , Metabolism , Hemagglutinins, Viral , Metabolism , Humans , Measles virus , Virulence , Physiology , Membrane Cofactor Protein , Metabolism , Membrane Fusion , Membrane Fusion Proteins , Metabolism , Receptors, Cell Surface , Metabolism , Receptors, Virus , Metabolism , Signaling Lymphocytic Activation Molecule Family Member 1
9.
Protein & Cell ; (12): 502-511, 2013.
Article in English | WPRIM | ID: wpr-757783

ABSTRACT

Avian influenza A virus continues to pose a global threat with occasional H5N1 human infections, which is emphasized by a recent severe human infection caused by avian-origin H7N9 in China. Luckily these viruses do not transmit efficiently in human populations. With a few amino acid substitutions of the hemagglutinin H5 protein in the laboratory, two H5 mutants have been shown to obtain an air-borne transmission in a mammalian ferret model. Here in this study one of the mutant H5 proteins developed by Kawaoka's group (VN1203mut) was expressed in a baculovirus system and its receptor-binding properties were assessed. We herein show that the VN1203mut had a dramatically reduced binding affinity for the avian α2,3-linkage receptor compared to wild type but showed no detectable increase in affinity for the human α2,6-linkage receptor, using Surface Plasmon Resonance techonology. Further, the crystal structures of the VN1203mut and its complexes with either human or avian receptors demonstrate that the VN1203mut binds the human receptor in the same binding manner (cis conformation) as seen for the HAs of previously reported 1957 and 1968 pandemic influenza viruses. Our receptor binding and crystallographic data shown here further confirm that the ability to bind the avian receptor has to decrease for a higher human receptor binding affinity. As the Q226L substitution is shown important for obtaining human receptor binding, we suspect that the newly emerged H7N9 binds human receptor as H7 has a Q226L substitution.


Subject(s)
Air Microbiology , Crystallography, X-Ray , Glycosylation , Hemagglutinin Glycoproteins, Influenza Virus , Chemistry , Genetics , Metabolism , Humans , Influenza A Virus, H5N1 Subtype , Chemistry , Metabolism , Influenza A Virus, H7N9 Subtype , Chemistry , Models, Molecular , Mutant Proteins , Chemistry , Genetics , Metabolism , Protein Binding , Protein Stability , Receptors, Cell Surface , Genetics , Metabolism , Solubility , Surface Plasmon Resonance , Temperature
10.
Protein & Cell ; (12): 761-770, 2013.
Article in English | WPRIM | ID: wpr-757767

ABSTRACT

Leukocyte immunoglobulin-like receptors (LILRs), also called CD85s, ILTs, or LIRs, are important mediators of immune activation and tolerance that contain tandem immunoglobulin (Ig)-like folds. There are 11 (in addition to two pseudogenes) LILRs in total, two with two Ig-like domains (D1D2) and the remaining nine with four Ig-like domains (D1D2D3D4). Thus far, the structural features of the D1D2 domains of LILR proteins are well defined, but no structures for the D3D4 domains have been reported. This is a very important field to be studied as it relates to the unknown functions of the D3D4 domains, as well as their relative orientation to the D1D2 domains on the cell surface. Here, we report the crystal structures of the D3D4 domains of both LILRB1 and LILRB2. The two Ig-like domains of both LILRB1-D3D4 and LILRB2-D3D4 are arranged at an acute angle (∼60°) to form a bent structure, resembling the structures of natural killer inhibitory receptors. Based on these two D3D4 domain structures and previously reported D1D2/HLA I complex structures, two alternative models of full-length (four Ig-like domains) LILR molecules bound to HLA I are proposed.


Subject(s)
Amino Acid Sequence , Antigens, CD , Chemistry , Crystallography, X-Ray , Histocompatibility Antigens Class I , Chemistry , Humans , Immunoglobulins , Chemistry , Leukocyte Immunoglobulin-like Receptor B1 , Membrane Glycoproteins , Chemistry , Models, Molecular , Peptides , Chemistry , Metabolism , Protein Binding , Protein Structure, Tertiary , Receptors, Immunologic , Chemistry , Signal Transduction
11.
Protein & Cell ; (12): 846-853, 2013.
Article in English | WPRIM | ID: wpr-757551

ABSTRACT

In June 2013, the first human H6N1 influenza virus infection was confirmed in Taiwan. However, the origin and molecular characterization of this virus, A/Taiwan/2/2013 (H6N1), have not been well studied thus far. In the present report, we performed phylogenetic and coalescent analyses of this virus and compared its molecular profile/characteristics with other closely related strains. Molecular characterization of H6N1 revealed that it is a typical avian influenza virus of low pathogenicity, which might not replicate and propagate well in the upper airway in mammals. Phylogenetic analysis revealed that the virus clusters with A/chicken/Taiwan/A2837/2013 (H6N1) in seven genes, except PB1. For the PB1 gene, A/Taiwan/2/2013 was clustered with a different H6N1 lineage from A/chicken/Taiwan/ A2837/2013. Although a previous study demonstrated that the PB2, PA, and M genes of A/Taiwan/2/2013 might be derived from the H5N2 viruses, coalescent analyses revealed that these H5N2 viruses were derived from more recent strains than that of the ancestor of A/Taiwan/2/2013. Therefore, we propose that A/Taiwan/2/2013 is a reassortant from different H6N1 lineages circulating in chickens in Taiwan. Furthermore, compared to avian isolates, a single P186L (H3 numbering) substitution in the hemagglutinin H6 of the human isolate might increase the mammalian receptor binding and, hence, this strain's pathogenicity in humans. Overall, human infection with this virus seems an accidental event and is unlikely to cause an influenza pandemic. However, its co-circulation and potential reassortment with other influenza subtypes are still worthy of attention.


Subject(s)
Amino Acid Sequence , Amino Acid Substitution , Animals , Hemagglutinin Glycoproteins, Influenza Virus , Chemistry , Genetics , Humans , Influenza A Virus, H5N2 Subtype , Genetics , Physiology , Influenza A virus , Genetics , Physiology , Influenza, Human , Epidemiology , Virology , Laboratories , Models, Molecular , Molecular Sequence Data , Phylogeny , Poultry , Virology , Protein Conformation , Taiwan , Epidemiology , Viral Proteins , Genetics
12.
Protein & Cell ; (12): 769-780, 2012.
Article in English | WPRIM | ID: wpr-757857

ABSTRACT

Enolase is a conserved cytoplasmic metalloenzyme existing universally in both eukaryotic and prokaryotic cells. The enzyme can also locate on the cell surface and bind to plasminogen, via which contributing to the mucosal surface localization of the bacterial pathogens and assisting the invasion into the host cells. The functions of the eukaryotic enzymes on the cell surface expression (including T cells, B cells, neutrophils, monocytoes, neuronal cells and epithelial cells) are not known. Streptococcus suis serotype 2 (S. suis 2, SS2) is an important zoonotic pathogen which has recently caused two large-scale outbreaks in southern China with severe streptococcal toxic shock syndrome (STSS) never seen before in human sufferers. We recently identified the SS2 enolase as an important protective antigen which could protect mice from fatal S.suis 2 infection. In this study, a 2.4-angstrom structure of the SS2 enolase is solved, revealing an octameric arrangement in the crystal. We further demonstrated that the enzyme exists exclusively as an octamer in solution via a sedimentation assay. These results indicate that the octamer is the biological unit of SS2 enolase at least in vitro and most likely in vivo as well. This is, to our knowledge, the first comprehensive characterization of the SS2 enolase octamer both structurally and biophysically, and the second octamer enolase structure in addition to that of Streptococcus pneumoniae. We also investigated the plasminogen binding property of the SS2 enzyme.


Subject(s)
Amino Acid Sequence , Binding Sites , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Sequence Data , Phosphopyruvate Hydratase , Chemistry , Metabolism , Plasminogen , Metabolism , Protein Multimerization , Protein Structure, Quaternary , Solutions , Species Specificity , Streptococcus suis
13.
Chinese Journal of Biotechnology ; (12): 1370-1377, 2012.
Article in Chinese | WPRIM | ID: wpr-342389

ABSTRACT

Wolynes argued that the track of a protein's folding was directed by the tendency of lowering its energy, and thus when a local minimum of its energy was reached, a relatively stable conformation was formed. However not all of the local minimums will lead the protein to a biologically useful conformation, for those otherwise are called energy traps. Wolynes energy landscape theory and natural selection have well explained the high efficiency of protein folding in vivo, instead of being stuck in energy traps. As to whether a protein can assume different conformations with the same bioactivity, there is no clear answer yet. In this paper, two conformational states of a pHLA-A*2402 are discovered after refolding, and by studying their interactions with TCR and CD8alphaalpha, two conformations of pHLA-A*2402 are confirmed of having escaped from natural selection.


Subject(s)
CD8 Antigens , Chemistry , Energy Metabolism , HLA-A24 Antigen , Chemistry , Humans , Protein Conformation , Protein Folding , Receptors, Antigen, T-Cell , Chemistry
14.
Protein & Cell ; (12): 64-73, 2011.
Article in English | WPRIM | ID: wpr-757663

ABSTRACT

Human NUDT16 (hNUDT16) is a decapping enzyme initially identified as the human homolog to the Xenopus laevis X29. As a metalloenzyme, hNUDT16 relies on divalent cations for its cap-hydrolysis activity to remove m⁷GDP and m²²⁷GDP from RNAs. Metal also determines substrate specificity of the enzyme. So far, only U8 small nucleolar RNA (snoRNA) has been identified as the substrate of hNUDT16 in the presence of Mg²(+). Here we demonstrate that besides U8, hNUDT16 can also actively cleave the m⁷GDP cap from mRNAs in the presence of Mg²(+) or Mn²(+). We further show that hNUDT16 does not preferentially recognize U8 or mRNA substrates by our cross-inhibition and quantitative decapping assays. In addition, our mutagenesis analysis identifies several key residues involved in hydrolysis and confirms the key role of the REXXEE motif in catalysis. Finally an investigation into the subcellular localization of hNUDT16 revealed its abundance in both cytoplasm and nucleus. These findings extend the substrate spectrum of hNUDT16 beyond snoRNAs to also include mRNA, demonstrating the pleiotropic decapping activity of hNUDT16.


Subject(s)
Amino Acid Motifs , Biocatalysis , Cell Nucleus , Consensus Sequence , Cytoplasm , Metabolism , Guanosine Diphosphate , Metabolism , Histidine , Metabolism , Humans , Hydrolysis , Luciferases , Genetics , Magnesium , Metabolism , Manganese , Metabolism , Mutagenesis , Mutation , Pyrophosphatases , Chemistry , Genetics , Metabolism , RNA Caps , Chemistry , Metabolism , Pharmacology , RNA, Small Nucleolar , Chemistry , Metabolism , Pharmacology
15.
Protein & Cell ; (12): 997-1005, 2011.
Article in English | WPRIM | ID: wpr-757312

ABSTRACT

There is a great need for new vaccine development against influenza A viruses due to the drawbacks of traditional vaccines that are mainly prepared using embryonated eggs. The main component of the current split influenza A virus vaccine is viral hemagglutinin (HA) which induces a strong antibody-mediated immune response. To develop a modern vaccine against influenza A viruses, the current research has been focused on the universal vaccines targeting viral M2, NP and HA proteins. Crystallographic studies have shown that HA forms a trimer embedded on the viral envelope surface, and each monomer consists of a globular head (HA1) and a "rod-like" stalk region (HA2), the latter being more conserved among different HA subtypes and being the primary target for universal vaccines. In this study, we rationally designed the HA head based on the crystal structure of the 2009-pandemic influenza A (H1N1) virus HA as a model, tested its immunogenicity in mice, solved its crystal structure and further examined its immunological characteristics. The results show that the HA globular head can be easily prepared by in vitro refolding in an E. coli expression system, which maintains its intact structure and allows for the stimulation of a strong immune response. Together with recent reports on some similar HA globular head preparations we conclude that structure-based rational design of the HA globular head can be used for subtype-specific vaccines against influenza viruses.


Subject(s)
Animals , Antibodies, Viral , Allergy and Immunology , Crystallography, X-Ray , Drug Design , Female , Freund's Adjuvant , Hemagglutinin Glycoproteins, Influenza Virus , Genetics , Allergy and Immunology , Humans , Influenza A Virus, H1N1 Subtype , Genetics , Allergy and Immunology , Influenza Vaccines , Influenza, Human , Allergy and Immunology , Virology , Mice , Mice, Inbred BALB C , Models, Molecular , Protein Folding , Recombinant Proteins , Genetics , Allergy and Immunology , Structure-Activity Relationship , Vaccination , Vaccines, Subunit
16.
Protein & Cell ; (12): 250-258, 2011.
Article in English | WPRIM | ID: wpr-757102

ABSTRACT

NDM-1 (New Delhi metallo-beta-lactamase) gene encodes a metallo-beta-lactamase (MBL) with high carbapenemase activity, which makes the host bacterial strain easily dispatch the last-resort antibiotics known as carbapenems and cause global concern. Here we present the bioinformatics data showing an unexpected similarity between NDM-1 and beta-lactamase II from Erythrobacter litoralis, a marine microbial isolate. We have further expressed these two mature proteins in E. coli cells, both of which present as a monomer with a molecular mass of 25 kDa. Antimicrobial susceptibility assay reveals that they share similar substrate specificities and are sensitive to aztreonam and tigecycline. The conformational change accompanied with the zinc binding visualized by nuclear magnetic resonance, Zn(2+)-bound NDM-1, adopts at least some stable tertiary structure in contrast to the metal-free protein. Our work implies a close evolutionary relationship between antibiotic resistance genes in environmental reservoir and in the clinic, challenging the antimicrobial resistance monitoring.


Subject(s)
Amino Acid Sequence , Anti-Bacterial Agents , Pharmacology , Aztreonam , Pharmacology , Cephalosporinase , Chemistry , Genetics , Metabolism , Computational Biology , Methods , Drug Resistance, Bacterial , Genetics , Enzyme Stability , Evolution, Molecular , Minocycline , Pharmacology , Molecular Sequence Data , Phylogeny , Protein Structure, Tertiary , Sequence Homology, Nucleic Acid , Sphingomonadaceae , Genetics , Tigecycline , Zinc , Pharmacology , beta-Lactamases , Chemistry , Genetics , Metabolism
17.
Protein & Cell ; (12): 459-467, 2010.
Article in English | WPRIM | ID: wpr-757741

ABSTRACT

Influenza virus is the causative agent of the seasonal and occasional pandemic flu. The current H1N1 influenza pandemic, announced by the WHO in June 2009, is highly contagious and responsible for global economic losses and fatalities. Although the H1N1 gene segments have three origins in terms of host species, the virus has been named swine-origin influenza virus (S-OIV) due to a predominant swine origin. 2009 S-OIV has been shown to highly resemble the 1918 pandemic virus in many aspects. Hemagglutinin is responsible for the host range and receptor binding of the virus and is therefore a primary indicator for the potential of infection. Primary sequence analysis of the 2009 S-OIV hemagglutinin (HA) reveals its closest relationship to that of the 1918 pandemic influenza virus, however, analysis at the structural level is necessary to critically assess the functional significance. In this report, we report the crystal structure of soluble hemagglutinin H1 (09H1) at 2.9 Å, illustrating that the 09H1 is very similar to the 1918 pandemic HA (18H1) in overall structure and the structural modules, including the five defined antiboby (Ab)-binding epitopes. Our results provide an explanation as to why sera from the survivors of the 1918 pandemics can neutralize the 2009 S-OIV, and people born around the 1918 are resistant to the current pandemic, yet younger generations are more susceptible to the 2009 pandemic.


Subject(s)
Animals , Cloning, Molecular , Crystallography, X-Ray , Hemagglutinin Glycoproteins, Influenza Virus , Chemistry , Genetics , Allergy and Immunology , Influenza A Virus, H1N1 Subtype , Chemistry , Genetics , Allergy and Immunology , Models, Molecular , Protein Conformation , Swine , Virology
18.
Protein & Cell ; (12): 153-160, 2010.
Article in English | WPRIM | ID: wpr-757718

ABSTRACT

PD-L1 is a member of the B7 protein family, most of whose members so far were identified as dimers in a solution and crystalline state, either complexed or uncomplexed with their ligand(s). The binding of PD-L1 with its receptor PD-1 (CD279) delivers an inhibitory signal regulating the T cell function. Simultaneously with the Garboczi group, we successfully solved another structure of human PD-L1 (hPD-L1). Our protein crystallized in the space group of C222(1) with two hPD-L1 molecules per asymmetric unit. After comparison of reported B7 structures, we have found some intrinsic factors involved in the interaction of these two molecules. Based on these results, we tend to believe this uncomplexed hPD-L1 structure demonstrated its potential dimeric state in solution, although it could just be an evolutionary relic, too weak to be detected under present technology, or still a functional unit deserved our attentions.


Subject(s)
Antigens, CD , Chemistry , Allergy and Immunology , B7-H1 Antigen , Crystallography, X-Ray , Evolution, Molecular , Humans , Protein Multimerization , Protein Structure, Quaternary , Protein Structure, Secondary , T-Lymphocytes , Chemistry , Allergy and Immunology
19.
Protein & Cell ; (12): 944-955, 2010.
Article in English | WPRIM | ID: wpr-757683

ABSTRACT

Influenza virus contains three integral membrane proteins: haemagglutinin, neuraminidase, and matrix protein (M1 and M2). Among them, M2 protein functions as an ion channel, important for virus uncoating in endosomes of virus-infected cells and essential for virus replication. In an effort to explore potential new functions of M2 in the virus life cycle, we used yeast two-hybrid system to search for M2-associated cellular proteins. One of the positive clones was identified as human Hsp40/Hdj1, a DnaJ/Hsp40 family protein. Here, we report that both BM2 (M2 of influenza B virus) and A/M2 (M2 of influenza A virus) interacted with Hsp40 in vitro and in vivo. The region of M2-Hsp40 interaction has been mapped to the CTD1 domain of Hsp40. Hsp40 has been reported to be a regulator of PKR signaling pathway by interacting with p58(IPK) that is a cellular inhibitor of PKR. PKR is a crucial component of the host defense response against virus infection. We therefore attempted to understand the relationship among M2, Hsp40 and p58(IPK) by further experimentation. The results demonstrated that both A/M2 and BM2 are able to bind to p58(IPK) in vitro and in vivo and enhance PKR autophosphorylation probably via forming a stable complex with Hsp40 and P58(IPK), and consequently induce cell death. These results suggest that influenza virus M2 protein is involved in p58(IPK) mediated PKR regulation during influenza virus infection, therefore affecting infected-cell life cycle and virus replication.


Subject(s)
HSP40 Heat-Shock Proteins , Genetics , Metabolism , Humans , Orthomyxoviridae , Genetics , Metabolism , Phosphorylation , Protein Binding , Genetics , Signal Transduction , Genetics , Two-Hybrid System Techniques , Viral Matrix Proteins , Metabolism , Virus Replication , Genetics , Virus Uncoating , eIF-2 Kinase , Metabolism
20.
Chinese Journal of Biotechnology ; (12): 1461-1472, 2010.
Article in Chinese | WPRIM | ID: wpr-351572

ABSTRACT

Throughout human history, pandemic bacterial diseases such as the plague and tuberculosis have posed an enormous threat to human beings. The discovery of antibiotics has provided us with powerful arsenal for the defense against bacterial infections. However, bacteria are acquiring more and more resistance genes to shield off antibiotics through mutation and horizontal gene transfer. Therefore, novel antibiotics must be produced and the arms race between bacterial pathogens and antibiotics is becoming increasingly intense. Recently, researchers have found that plasmids carrying a new metallo-beta-lactamase gene, blaNDM-1, and many other antibiotics resistance genes can easily spread through bacterial populations and confer recipient stains resistance to nearly all of the current antibiotics. It is a threat to the human health and a great challenge for our medical science, which we are facing. We need to find new ways to fight and win this arms racing.


Subject(s)
Anti-Bacterial Agents , Pharmacology , Bacteria , Genetics , Drug Resistance, Bacterial , Genetics , Gene Transfer, Horizontal , Mutation , Plasmids , Genetics , beta-Lactamases , Genetics
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