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One or more keywords matched the following properties of Tang, Wei-Jen
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keywords Bacterial pathogenesis
overview My laboratory focuses on applying integrated structural and biochemical approaches to elucidate the molecular basis of protein-protein interactions and protein-ligand/drug interactions that are relevant to human health and diseases. Armed with such knowledge, we then apply chemical and pharmacological approaches to develop therapeutic innovations. Currently, we are studying the following proteins: Amyloid peptide-degrading proteases: Metalloproteases, insulin degrading enzyme (IDE) and presequence protease (PreP) degrade amyloid beta, a peptide vital for the progression of Alzheimer's disease. IDE is also involved in the clearance of insulin, amylin, and glucagon, pancreatic peptides for glucose homeostasis. PreP is involved in the clearance of mitochondrial importing presequence peptides, which are toxic to mitochondria. Our structures of human IDE in complex with its substrates elucidate the molecular basis of how IDE recognizes amyloidogenic peptides and offers a basis to explore IDE-based therapeutics in controlling cerebral amyloid beta accumulation and blood sugar levels. Our structures of human PreP reveal how PreP recognizes amyloid beta. Future directions in studying proteases that degrade amyloid peptides include exploration into the molecular basis in the regulation of catalysis of IDE, PreP, and other amyloid-peptide degrading proteases such as neprilysin and endothelin converting enzymes, discovery of small molecule activator and inhibitor leads, and protein engineering for therapies. Chemokines: Inflammation is vital in the progression of many chronic human illnesses. Proinflammatory chemokines, e.g., CCL5 and CCL3, play key roles in modulating inflammation and consequently affect disease progression such as cancer and immunological disorders. In addition, CCR5, the CCL3 and CCL5 cognate receptor, is a co-receptor for HIV virus. Self-association and binding to extracellular glycan of chemokines are key regulatory steps in controlling chemokine functions. Our structural and biochemical analyses of CCL3 and CCL5 have elucidated the structural basis of CCL3 and CCL5 oligomerization and binding to glycosaminoglycan (GAG). Future directions include the elucidation of the molecular basis of how oligomerization and GAG binding regulates chemokine functions and the development of small molecules to modulate inflammation. Bacterial toxins secreted by human bacterial pathogens: We study bacterial adenylyl cyclase toxins that are only active upon entering into target cells and are associated with cellular proteins that serve as the activator. These adenylyl cyclase toxins raise the intracellular cyclic AMP (cAMP) of their host cells to benefit bacterial propagation. We have studied three adenylyl cyclase toxins, edema factor (EF) secreted by bacteria that cause anthrax, CyaA secreted bacteria that cause whooping cough, and ExoY injected by Pseudomonas aeruginosa, an opportunistic pathogens for nosocomial infections. Both EF and CyaA bind the cellular calcium sensor, calmodulin, with high affinity. Our structural and biochemical analyses have elucidated how calmodulin binds and activates EF and CyaA. ExoY is activated by binding to F-actin and we show that ExoY induces the bundling of F-actin. We will continue to address the structural basis for the interaction of these toxins with their cellular partners. We will also explore the therapeutic potential of adenylyl cyclase toxins in human diseases as well. The incident of bioterrorism-related anthrax in 2001 has moved the challenge against anthrax from an obscure agricultural problem to the center of bio-defense. Given the ease of making antibiotic-resistant anthrax strains and unknown enemies, the best defense against anthrax is to build up a battery of possible antidotes against anthrax that can be rapidly scaled up for production in response to the low probability, high impact incidence of anthrax-related bioterrorism.
One or more keywords matched the following items that are connected to Tang, Wei-Jen
Item TypeName
Concept Antigens, Bacterial
Concept Bacterial Infections
Concept Bacterial Toxins
Concept Bacterial Proteins
Concept Spores, Bacterial
Concept Gene Expression Regulation, Bacterial
Concept Bacterial Physiological Phenomena
Academic Article Crystallization and preliminary X-ray study of the edema factor exotoxin adenylyl cyclase domain from Bacillus anthracis in the presence of its activator, calmodulin.
Academic Article Selective inhibition of anthrax edema factor by adefovir, a drug for chronic hepatitis B virus infection.
Academic Article Anthrax edema toxin inhibits endothelial cell chemotaxis via Epac and Rap1.
Academic Article Bacillus anthracis edema toxin causes extensive tissue lesions and rapid lethality in mice.
Academic Article Protein-protein docking and analysis reveal that two homologous bacterial adenylyl cyclase toxins interact with calmodulin differently.
Academic Article Spatial localization of bacteria controls coagulation of human blood by 'quorum acting'.
Academic Article Cellular functions and X-ray structure of anthrolysin O, a cholesterol-dependent cytolysin secreted by Bacillus anthracis.
Academic Article Anthrax edema factor potency depends on mode of cell entry.
Academic Article The role of anthrolysin O in gut epithelial barrier disruption during Bacillus anthracis infection.
Academic Article An extended conformation of calmodulin induces interactions between the structural domains of adenylyl cyclase from Bacillus anthracis to promote catalysis.
Academic Article Structural basis for the activation of anthrax adenylyl cyclase exotoxin by calmodulin.
Academic Article Discovery of a small molecule that inhibits the interaction of anthrax edema factor with its cellular activator, calmodulin.
Academic Article Structure of anthrax edema factor-calmodulin-adenosine 5'-(alpha,beta-methylene)-triphosphate complex reveals an alternative mode of ATP binding to the catalytic site.
Academic Article Structural and kinetic analyses of the interaction of anthrax adenylyl cyclase toxin with reaction products cAMP and pyrophosphate.
Academic Article Chemical screening by mass spectrometry to identify inhibitors of anthrax lethal factor.
Academic Article Calcium-independent calmodulin binding and two-metal-ion catalytic mechanism of anthrax edema factor.
Academic Article The adenylyl cyclase activity of anthrax edema factor.
Grant Intervention against anthrax edema factor (EF)
Academic Article Rapid Discovery and Characterization of Synthetic Neutralizing Antibodies against Anthrax Edema Toxin.
Academic Article Anthrax toxin-induced shock in rats is associated with pulmonary edema and hemorrhage.
Academic Article The case for developing consensus standards for research in microbial pathogenesis: Bacillus anthracis toxins as an example.
Academic Article Distinct interactions of 2'- and 3'-O-(N-methyl)anthraniloyl-isomers of ATP and GTP with the adenylyl cyclase toxin of Bacillus anthracis, edema factor.
Academic Article Anthrax toxins induce shock in rats by depressed cardiac ventricular function.
Academic Article Anthrax edema toxin sensitizes DBA/2J mice to lethal toxin.
Academic Article Different Roles of N-Terminal and C-Terminal Domains in Calmodulin for Activation of Bacillus anthracis Edema Factor.
Academic Article Inhibition of the adenylyl cyclase toxin, edema factor, from Bacillus anthracis by a series of 18 mono- and bis-(M)ANT-substituted nucleoside 5'-triphosphates.
Academic Article Noninvasive imaging technologies reveal edema toxin as a key virulence factor in anthrax.
Academic Article Molecular analysis of the interaction of anthrax adenylyl cyclase toxin, edema factor, with 2'(3')-O-(N-(methyl)anthraniloyl)-substituted purine and pyrimidine nucleotides.
Academic Article Lethal and edema toxins of anthrax induce distinct hemodynamic dysfunction.
Academic Article Anthrax edema toxin cooperates with lethal toxin to impair cytokine secretion during infection of dendritic cells.
Academic Article Anthrax toxins suppress T lymphocyte activation by disrupting antigen receptor signaling.
Academic Article Calcium dependence of the interaction between calmodulin and anthrax edema factor.
Academic Article Pseudomonas aeruginosa exoenzyme Y directly bundles actin filaments.
Academic Article Structural analysis of Mycobacterium tuberculosis M13 metalloprotease Zmp1 open states.
Search Criteria
  • Bacterial
  • pathogenesis