Corrigendum to “Crystal Structures of Δ1-Pyrroline-5-Carboxylate Reductase from Human Pathogens Neisseria meningitides and Streptococcus pyogenes” [J. Mol. Biol. (2005) 354, 91–106]

2006 ◽  
Vol 357 (3) ◽  
pp. 1050
Author(s):  
B. Nocek ◽  
C. Chang ◽  
H. Li ◽  
L. Lezondra ◽  
D. Holzle ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Streptococcus Pyogenes ◽  
Human Pathogens ◽  
Neisseria Meningitides ◽  
Carboxylate Reductase

scholarly journals Human Keratinocyte Response to Superantigens

mSphere ◽  
2020 ◽  
Vol 5 (5) ◽  
Author(s):  
Patrick M. Schlievert ◽  
Francoise A. Gourronc ◽  
Donald Y. M. Leung ◽  
Aloysius J. Klingelhutz
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pyogenes ◽  
Skin Barrier ◽  
Human Keratinocytes ◽  
Human Diseases ◽  
Human Pathogens ◽  
Chemokine Production ◽  
Content Type ◽  
Human Keratinocyte ◽  
Stimulation Of

ABSTRACT Staphylococcus aureus and Streptococcus pyogenes are significant human pathogens, causing infections at multiple body sites, including across the skin. Both are organisms that cause human diseases and secrete superantigens, including toxic shock syndrome toxin-1 (TSST-1), staphylococcal enterotoxins (SEs), and streptococcal pyrogenic exotoxins (SPEs). On the skin, human keratinocytes represent the first cell type to encounter these superantigens. We employed transcriptome sequencing (RNA-seq) to evaluate the human primary keratinocyte response to both TSST-1 and staphylococcal enterotoxin B (SEB) in triplicate analyses. Both superantigens caused large numbers of genes to be up- and downregulated. The genes that exhibited 2-fold differential gene expression compared to vehicle-treated cells, whether up- or downregulated, totaled 5,773 for TSST-1 and 4,320 for SEB. Of these, 4,482 were significantly upregulated by exposure of keratinocytes to TSST-1, whereas 1,291 were downregulated. For SEB, expression levels of 3,785 genes were upregulated, whereas those of 535 were downregulated. There was the expected high overlap in both upregulation (3,412 genes) and downregulation (400 genes). Significantly upregulated genes included those associated with chemokine production, with the possibility of stimulation of inflammation. We also tested an immortalized human keratinocyte line, from a different donor, for chemokine response to four superantigens. TSST-1 and SEB caused production of interleukin-8 (IL-8), MIP-3α, and IL-33. SPEA and SPEC were evaluated for stimulation of expression of IL-8 as a representative chemokine; both stimulated production of IL-8. IMPORTANCE Staphylococcus aureus and Streptococcus pyogenes are common human pathogens, causing infections that include the skin. Both pathogens produce a family of secreted toxins called superantigens, which have been shown to be important in human diseases. The first cell types encountered by superantigens on skin are keratinocytes. Our studies demonstrated, that the human keratinocyte pathway, among other pathways, responds to superantigens with production of chemokines, setting off inflammation. This inflammatory response may be harmful, facilitating opening of the skin barrier.

scholarly journals Crystal structures of full length DENV4 NS2B-NS3 reveal the dynamic interaction between NS2B and NS3

2020 ◽  
Author(s):  
Wint Wint Phoo ◽  
Abbas El Sahili ◽  
ZhenZhen Zhang ◽  
Ming Wei Chen ◽  
Chong Wai Liew ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Negative Impact ◽  
Full Length ◽  
Structural Protein ◽  
Human Pathogens ◽  
Multifunctional Protein ◽  
Closed Conformation ◽  
Pancreatic Trypsin Inhibitor ◽  
And Function ◽  
Ns3 Protease

AbstractFlavivirus is a genus of emerging and re-emerging arboviruses which include many significant human pathogens. Non-structural protein 3 (NS3), a multifunctional protein with N-terminal protease and C-terminal helicase, is essential in viral replication. The NS3 protease together with NS2B cofactor is an attractive antiviral target. A construct with an artificial glycine linker connecting the NS2B cofactor and NS3 protease has been used for structural, biochemical and drug-screening studies. The effect of this linker on dynamics and enzymatic activity of the protease was studied by several biochemical and NMR methods but the findings remained inconclusive. Here, we designed constructs of NS2B cofactor joined to full length DENV4 NS3 in three different manners, namely bNS2B47NS3 (bivalent), eNS2B47NS3(enzymatically cleavable) and gNS2B47NS3 (glycine-rich G4SG4 linker). We report the first crystal structures of linked and unlinked full-length NS2B-NS3 enzyme in its free state and also in complex with Bovine Pancreatic Trypsin Inhibitor (BPTI). These structures demonstrate that the NS2B-NS3 protease mainly adopts a closed conformation. BPTI binding is not essential to but favors the closed conformation by interacting with both NS2B and NS3. The artificial linker between NS2B and NS3 tends to induce the open conformation and interfere with the protease activity. This negative impact on the enzyme structure and function is restricted to the protease domain as the ATPase activities of these constructs are not affected.

scholarly journals The Signal Recognition Particle Pathway Is Required for Virulence in Streptococcus pyogenes

2008 ◽  
Vol 76 (6) ◽  
pp. 2612-2619 ◽  
Author(s):  
Jason W. Rosch ◽  
Luis Alberto Vega ◽  
John M. Beyer ◽  
Ada Lin ◽  
Michael G. Caparon
Keyword(s):  
Streptococcus Pyogenes ◽  
Signal Recognition Particle ◽  
Growth Defect ◽  
Signal Recognition ◽  
Human Pathogens ◽  
Gram Positive ◽  
Zebrafish Model ◽  
Gram Positive Bacteria

ABSTRACT The signal recognition particle (SRP) pathway is a universally conserved pathway for targeting polypeptides for secretion via the cotranslational pathway. In particular, the SRP pathway is thought to be the main mechanism for targeting polypeptides in gram-positive bacteria, including a number of important human pathogens. Though widely considered to be an essential cellular component, recent advances have indicated this pathway may be dispensable in gram-positive bacteria of the genus Streptococcus under in vitro conditions. However, its importance for the pathogenesis of streptococcal disease is unknown. In this study, we investigated the importance of the SRP pathway for virulence factor secretion in the human pathogen Streptococcus pyogenes. While the SRP pathway was not found to be essential for viability in vitro, SRP mutants demonstrated a medium-specific growth defect that could be rescued by the addition of glucose. We also observed that a distinct subset of virulence factors were dependent upon the SRP pathway for secretion, whereas others were completely independent of this pathway. Significantly, deletion of the SRP pathway resulted in mutants that were highly attenuated in both a zebrafish model of necrotic myositis and a murine subcutaneous ulcer model, highlighting the importance of this pathway in vivo. These studies emphasize the importance of the SRP pathway for the in vivo survival and pathogenesis of S. pyogenes.

Crystal structures of SCP2-thiolases of Trypanosomatidae, human pathogens causing widespread tropical diseases: the importance for catalysis of the cysteine of the unique HDCF loop

2013 ◽  
Vol 455 (1) ◽  
pp. 119-130 ◽  
Author(s):  
Rajesh K. Harijan ◽  
Tiila R. Kiema ◽  
Mikael P. Karjalainen ◽  
Neelanjana Janardan ◽  
M. R. N. Murthy ◽  
...  
Keyword(s):  
Reaction Mechanism ◽  
Crystal Structures ◽  
Biosynthetic Pathway ◽  
Tropical Diseases ◽  
Biosynthetic Enzyme ◽  
Human Pathogens ◽  
Unique Reaction ◽  
Trypanosomatid Parasites ◽  
Sterol Biosynthetic Pathway

Structural enzymological studies of trypanosomatid SCP2-thiolase reveal its unique reaction mechanism. These studies suggest that this enzyme is a biosynthetic enzyme, possibly involved in the sterol biosynthetic pathway, which is essential in the human pathogenic stages of some trypanosomatid parasites.

scholarly journals Selective binding of small molecules to Vibrio cholerae DsbA offers a starting point for the design of novel antibacterials

2021 ◽  
Author(s):  
Geqing Wang ◽  
Biswaranjan Mohanty ◽  
Martin Williams ◽  
Bradley Doak ◽  
Rabeb Dhouib ◽  
...  
Keyword(s):  
Vibrio Cholerae ◽  
Crystal Structures ◽  
Small Molecule ◽  
Sodium Taurocholate ◽  
Structural Basis ◽  
Human Pathogens ◽  
X Ray ◽  
X Ray Crystallography ◽  
Hydrophobic Groove ◽  
Starting Point

DsbA enzymes catalyze oxidative folding of proteins that are secreted into the periplasm of Gram-negative bacteria, and they are indispensable for the virulence of human pathogens such as Vibrio cholerae and Escherichia coli. Therefore, targeting DsbA represents an attractive approach to control bacterial virulence. X-ray crystal structures reveal that DsbA enzymes share a similar fold, however, the hydrophobic groove adjacent to the active site, which is implicated in substrate binding, is shorter and flatter in the structure of V. cholerae DsbA (VcDsbA) compared to E. coli DsbA (EcDsbA). The flat and largely featureless nature of this hydrophobic groove is challenging for the development of small molecule inhibitors. Using fragment-based screening approaches, we have identified a novel small molecule, based on the benzimidazole scaffold, that binds to the hydrophobic groove of oxidized VcDsbA with a KD of 446 ± 10 µM. The same benzimidazole compound has ~8-fold selectivity for VcDsbA over EcDsbA and binds to oxidized EcDsbA, with KD > 3.5 mM. We generated a model of the benzimidazole complex with VcDsbA using NMR data but were unable to determine the structure of the benzimidazole bound EcDsbA using either NMR or X-ray crystallography. Therefore, a structural basis for the observed selectivity is unclear. To better understand ligand binding to these two enzymes we crystallized each of them in complex with a known ligand, the bile salt sodium taurocholate. The crystal structures show that taurocholate adopts different binding poses in complex with VcDsbA and EcDsbA, and reveals the protein-ligand interactions that stabilize the different modes of binding. This work highlights the capacity of fragment-based drug discovery to identify inhibitors of challenging protein targets. In addition, it provides a starting point for development of more potent and specific VcDsbA inhibitors that act through a novel anti-virulence mechanism.

scholarly journals Crystal Structures of Δ1-Piperideine-2-carboxylate/Δ1-Pyrroline-2-carboxylate Reductase Belonging to a New Family of NAD(P)H-dependent Oxidoreductases

2005 ◽  
Vol 280 (49) ◽  
pp. 40875-40884 ◽  
Author(s):  
Masaru Goto ◽  
Hisashi Muramatsu ◽  
Hisaaki Mihara ◽  
Tatsuo Kurihara ◽  
Nobuyoshi Esaki ◽  
...  
Keyword(s):  
Crystal Structures ◽  
New Family ◽  
Carboxylate Reductase
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