Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0016632 (Fox)
 1,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infection by hepatitis C viruses (HCVs) is a serious medical problem with no broadly effective treatment available for the progression of chronic hepatitis. The catalytic activity of a viral serine protease located in the N-terminal one-third of nonstructural protein 3 (NS3) is required for polyprotein processing at four site-specific junctions. The three-dimensional crystal structure of the NS3-NS4A co-complex [Kim, J. L., Morgenstern, K. A., Lin, C., Fox, T., Dwyer, M. D., Landro, J. A., Chambers, S. P., Markland, W., Lepre, C. A., O'Malley, E. T., Harbeson, S. L., Rice, C. M., Murcko, M. A., Caron, P. R., & Thomson, J. A. (1996) Cell 87, 343-355] delineates a small hydrophobic region within the 54-residue NS4A protein that intercalates with and makes extensive contacts to the core of the protease. The current investigation addresses the mechanism of NS3 protease catalytic activation by NS4A utilizing a small synthetic NS4A peptide (residues 1678-1691 of the virus polyprotein sequence) and the recombinantly expressed protease domain of NS3. The addition of NS4A dramatically increased NS3 kcat and kcat/Km catalytic parameters when measured against small peptide substrates representing the different site-specific junctions of the polyprotein. The catalytic effect of natural and non-natural amino acid substitutions at the P1 position in a 5A/5B peptide substrate was investigated. NS3-NS4A demonstrated a marked catalytic preference for the cysteine residue commonly found in authentic substrates. The pH dependence of the NS3 hydrolysis reaction is not affected by the presence of NS4A. This result suggests that NS4A does not change the pKa values of the active site residues of NS3 protease. A steady state kinetic analysis was performed and indicated that the binding of NS4A and the peptide substrate occurs in an ordered fashion during the catalytic cycle, with NS4A binding first. Two distinct kinetic classes of peptidyl inhibitors based upon the 5A/5B cleavage site were identified. An NS4A-independent class is devoid of prime residues. A second class of inhibitors is NS4A-dependent and contains a natural or non-natural cyclic amino acid substituted for the commonly found P1' residue serine. These inhibitors display an up to 80-fold increase in affinity for NS3 protease in the presence of NS4A. Sequential truncation of prime and P residues from this inhibitor class demonstrated the fact that the P4' and P1' residues are crucial for potent inhibition. The selectivity of this NS4A effect is interpreted using a model of the 5A/5B decapeptide substrate bound to the active site of the NS3-NS4A structure.
 ...
PMID:Mechanistic role of an NS4A peptide cofactor with the truncated NS3 protease of hepatitis C virus: elucidation of the NS4A stimulatory effect via kinetic analysis and inhibitor mapping. 923 76

This study was undertaken to investigate whether plasmacytoid dendritic cells (PDC) are involved in the generation of a higher proportion of CD4(+) and CD25(+) regulatory T (Treg) cells in chronic hepatitis B virus (HBV) infection compared with healthy patients. The amount, phenotype, and function of Treg cells in CD4(+) T cells primed by PDC from 46 chronic HBV patients, 25 healthy controls, and 10 individuals with resolved HBV infection were studied by flow cytometry, reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and proliferation assay. CD4(+) T cells primed by PDC from chronic HBV patients were more effective than CD4(+) T cells primed by PDC from the healthy controls and the resolved HBV patients in suppressing the hepatitis B core antigen-specific proliferation and the interferon production. The interleukin-10 and transforming growth factor-beta1 could also be detected in the supernatants of the PDC-primed CD4(+) T cells. A higher percentage of Treg cells, defined as CD4,CD25, CD45RO, and cytotoxic T-lymphocyte-associated antigen 4-positive cells, was detected within the population of CD4(+) T cells primed by PDC from chronic HBV patients compared with the healthy controls and individuals with resolved HBV infection. Accordingly, CD25(+) Treg cells from PDC-primed CD4(+) T cells displayed a high Fox P3 messenger RNA level. Depleting CD4(+) and CD25(+) Treg cells from CD4(+) T cells primed by PDC from the chronic HBV patients, the healthy volunteers, and the resolved HBV patients made PDC-primed CD4(+) T lose the capability in suppressing HBV-specific T cells. PDC from the patients with chronic HBV infection induced the generation of a higher proportion of CD4(+) and CD25(+) Treg cells compared with the healthy patients.
 ...
PMID:Human plasmacytoid dendritic cells from patients with chronic hepatitis B virus infection induce the generation of a higher proportion of CD4(+) and CD25(+) regulatory T cells compared with healthy patients. 1802 Dec 29