Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Folding thermodynamics of nine heterodimeric, parallel coiled coils were studied by isothermal titration calorimetry (ITC) and thermal unfolding circular dichroism measurements. The heterodimers were composed of an acidic and a basic 30-residue peptide, which when in isolation were monomeric and essentially unstructured. The reaction followed a two-state mechanism indicating that folding and association were coupled. delta Hfold, delta Sfold and delta Cp normalized per mol of residue were of the same magnitude as for monomeric globular proteins, hence the energetics of folding and association of the heterodimeric coiled coils was balanced similarly to the folding of a single polypeptide chain. Cavity creating Leu/Ala substitutions revealed strong and position-dependent energetic coupling between leucine residues in the hydrophobic core of the coiled coil. delta Gunfold (equivalent to -delta Gfold in the two-state reaction) was determined from thermal unfolding. Global stability curves were calculated according to the Gibbs-Helmholtz equation and using the combined free energy data from ITC and thermal unfolding. Maximum stabilities were between 15 and 37 degrees C and cold denaturation could be demonstrated by direct calorimetry. The stability curves were based on free energies of folding measured between 10 and 85 degrees C and under identical solvent conditions. This represents a novel experimental approach which circumvents the use of varying solvent conditions as is typically required to measure protein stability curves. Discrepancies were noticed between van't Hoff enthalpies deduced from thermal unfolding and measured by direct calorimetry. The discrepancies are thought to be due to residual ordered structure in the denatured single chains around room temperature but not near the transition midpoint temperature Tm. This demonstrates that over an extended temperature range the assumption of a common denatured state implicit in the van't Hoff analysis may not always be valid.
J Mol Biol 1996 Oct 25
PMID:Thermodynamic characterization of the coupled folding and association of heterodimeric coiled coils (leucine zippers). 891 11

Dental pulpal infection is most commonly caused by extensive dental caries. A principal driving force behind pulpal disease response appears to lie in the immune system's response to bacteria. However, the production of interleukin (IL)-1beta and IL-6 in human dental pulp (HDP) cells in response to lipopolysaccharide (LPS) has not been well characterized. We examined IL-1beta and IL-6 production in HDP cells by challenging with LPS from Porphyromonas endodontalis, which is a Gram-negative bacteria found in root canals. Our results presented here showed that when HDP cells were stimulated by LPS, the production of IL-6 always preceded that of IL-1beta. Since the IL-6 production was observed even in the presence of the IL-1beta receptor antagonist, we concluded IL-6 production was independent of the IL-1beta molecule in LPS-stimulated HDP cells. This idea was further supported by the results obtained from RT-PCR experiments, in which IL-6 mRNA, but not IL-1beta mRNA, was present in the RNA preparation isolated from the early stage of cells.
Biochem Mol Med 1996 Dec
PMID:Stimulation of interleukin-1beta-independent interleukin-6 production in human dental pulp cells by lipopolysaccharide. 898 36

We studied spectral autofluorescence characteristics of dental caries. A wide range of carious lesions revealed characteristic emission of endogenous fluorophores with strong fluorescence bands in the red spectral region when excited with 407 nm line radiation of a krypton ion laser. Healthy hard dental tissue exhibited no emission bands in the red. The fluorescence spectra, fluorescence excitation spectra as well as the reflectance spectra of carious lesions were found to be typical for fluorescent porphyrins, mainly protoporphyrin IX. A possible source of these porphyrins within carious tissues is bacterial biosynthesis. Non-invasive sensitive in vivo caries detection by means of appropriate excitation sources and porphyrin fluorescence detectors should be possible.
Cell Mol Biol (Noisy-le-grand) 1998 Dec
PMID:Laser-induced autofluorescence spectroscopy of dental caries. 987 16

Dental caries and periodontitis, although generally not life threatening, are nevertheless of significant importance. An understanding of the molecular nature of these diseases could aid the development of novel methods of prevention and control, and increase our knowledge of their etiology. The identification of virulence factors in oral bacteria could lead to the development of vaccines directed against these organisms, the design of inhibitors of biofilm formation, and the development of replacement therapy strategies.
Curr Issues Mol Biol 2001 Apr
PMID:Virulence properties of oral bacteria: impact of molecular biology. 1147 73

Cavity complementation has been observed in many proteins, where an appropriate small molecule binds to a cavity-forming mutant. Here, the binding of compounds to the W191G cavity mutant of cytochrome c peroxidase is characterized by X-ray crystallography and binding thermodynamics. Unlike cavities created by removal of hydrophobic side-chains, the W191G cavity does not bind neutral or hydrophobic compounds, but displays a strong specificity for heterocyclic cations, consistent with the role of the protein to stabilize a tryptophan radical at this site. Ligand dissociation constants for the protonated cationic state ranged from 6 microM for 2-amino-5-methylthiazole to 1 mM for neutral ligands, and binding was associated with a large enthalpy-entropy compensation. X-ray structures show that each of 18 compounds with binding behavior bind specifically within the artificial cavity and not elsewhere in the protein. The compounds make multiple hydrogen bonds to the cavity walls using a subset of the interactions seen between the protein and solvent in the absence of ligand. For all ligands, every atom that is capable of making a hydrogen bond does so with either protein or solvent. The most often seen interaction is to Asp235, and most compounds bind with a specific orientation that is defined by their ability to interact with this residue. Four of the ligands do not have conventional hydrogen bonding atoms, but were nevertheless observed to orient their most polar CH bond towards Asp235. Two of the larger ligands induce disorder in a surface loop between Pro190 and Asn195 that has been identified as a mobile gate to cavity access. Despite the predominance of hydrogen bonding and electrostatic interactions, the small variation in observed binding free energies were not correlated readily with the strength, type or number of hydrogen bonds or with calculated electrostatic energies alone. Thus, as with naturally occurring binding sites, affinities to W191G are likely to be due to a subtle balance of polar, non-polar, and solvation terms. These studies demonstrate how cavity complementation and judicious choice of site can be used to produce a protein template with an unusual ligand-binding specificity.
J Mol Biol 2002 Jan 25
PMID:Artificial protein cavities as specific ligand-binding templates: characterization of an engineered heterocyclic cation-binding site that preserves the evolved specificity of the parent protein. 1181 52

Antigens I/II are large multifunctional adhesins from oral viridans streptococci that exert immunomodulatory effects on human cells and play important roles in inflammatory disorders. Among them, Streptococcus mutans plays a major role in the initiation of dental caries. The structure of the V-region (SrV+, residues 464-840) of the antigen I/II of S. mutans has been determined using the multiwavelength anomalous diffraction phasing technique with seleno-methionine-substituted recombinant protein and subsequently refined at 2.4 A resolution. The crystal structure of SrV+ revealed a lectin-like fold that displays a putative preformed carbohydrate-binding site stabilized by a metal ion. Inhibition of this binding site may confer to humans a protection against dental caries and dissemination of the bacteria to extra-oral sites involved in life-threatening inflammatory diseases. This crystal structure constitutes a first step in understanding the structure-function relationship of antigens I/II and may help in delineating new preventive or therapeutic strategies against colonization of the host by oral streptococci.
J Mol Biol 2002 Apr 19
PMID:Crystal structure of the V-region of Streptococcus mutans antigen I/II at 2.4 A resolution suggests a sugar preformed binding site. 1205 77

Microbial interactions with host molecules, and programmed responses to host environmental stimuli, are critical for colonization and initiation of pathogenesis. Bacteria of the genus Streptococcus are primary colonizers of the human mouth. They express multiple cell-surface adhesins that bind salivary components and other oral bacteria and enable the development of polymicrobial biofilms associated with tooth decay and periodontal disease. However, the mechanisms by which streptococci invade dentine to infect the tooth pulp and periapical tissues are poorly understood. Here we show that production of the antigen I/II (AgI/II) family polypeptide adhesin and invasin SspA in Streptococcus gordonii is specifically upregulated in response to a collagen type I signal, minimally the tri-peptide Gly-Pro-Xaa (where Xaa is hydroxyproline or alanine). Increased AgI/II polypeptide expression promotes bacterial adhesion and extended growth of streptococcal cell chains along collagen type I fibrils that are characteristically found within dentinal tubules. These observations define a new model of host matrix signal-induced tissue penetration by bacteria and open the way for novel therapy opportunities for oral invasive diseases.
Mol Microbiol 2003 Oct
PMID:Host collagen signal induces antigen I/II adhesin and invasin gene expression in oral Streptococcus gordonii. 1461 82

To persist in the oral cavity, bacteria must be able to tolerate rapid and substantial environmental fluctuations, particularly in pH and nutrient source and availability. Various species of Streptococcus, one of the most abundant genera in the mouth, are associated with oral health, as well as with dental caries. Cariogenic streptococci depend on a biofilm lifestyle for survival and persistence in the oral cavity and have developed sophisticated mechanisms to cope with environmental stresses. Here, we analyze the primary factors that allow these bacteria to emerge as significant members of tooth biofilms during adverse conditions. Our focus is on the molecular mechanisms of biofilm formation, stress tolerance and sugar metabolism by pathogenic oral streptococci, mainly Streptococcus mutans. Overlaps in the roles and regulation of these virulence attributes are highlighted and areas of research that deserve further investigation are proposed.
Curr Issues Mol Biol 2005 Jan
PMID:Responses of cariogenic streptococci to environmental stresses. 1558 Jul 82

The proton translocating membrane ATPase of oral streptococci has been implicated in cytoplasmatic pH regulation, acidurance and cariogenicity. Studies have confirmed that Streptococcus mutans is the most frequently detected species in dental caries. A P-type ATPase that can act together with F(1)F(o)-ATPase in S. mutans membrane has been recently described. The main objective of this work is to characterize the kinetic of ATP hydrolysis of this P-type ATPase. The optimum pH for ATP hydrolysis is around 6.0. The dependence of P-type ATPase activity on ATP concentration reveals high (K(0.5)=0.27 mM) and low (K(0.5)=3.31 mM) affinity sites for ATP, exhibiting positive cooperativity and a specific activity of about 74 U/mg. Equimolar concentrations of ATP and magnesium ions display a behavior similar to that described for ATP concentration in Mg(2+) saturating condition (high affinity site, K(0.5)=0.10 mM, and low affinity site, K(0.5)=2.12 mM), exhibiting positive cooperativity and a specific activity of about 68 U/mg. Sodium, potassium, ammonium, calcium and magnesium ions stimulate the enzyme, showing a single saturation curve, all exhibiting positive cooperativities, whereas inhibition of ATPase activity is observed for zinc ions and EDTA. The kinetic characteristics reveal that this ATPase belongs to type IIIA, like the ones found in yeast and plants.
Comp Biochem Physiol B Biochem Mol Biol 2005 Apr
PMID:Kinetic characterization of P-type membrane ATPase from Streptococcus mutans. 1576 14

The causative agent of dental caries in humans, Streptococcus mutans, outcompetes other bacterial species in the oral cavity and causes disease by surviving acidic conditions in dental plaque. We have previously reported that the low-pH survival strategy of S. mutans includes the ability to induce a DNA repair system that appears to involve an enzyme with exonuclease functions (K. Hahn, R. C. Faustoferri, and R. G. Quivey, Jr., Mol. Microbiol 31:1489-1498, 1999). Here, we report overexpression of the S. mutans apurinic/apyrimidinic (AP) endonuclease, Smx, in Escherichia coli; initial characterization of its enzymatic activity; and analysis of an smx mutant strain of S. mutans. Insertional inactivation of the smx gene eliminates the low-pH-inducible exonuclease activity previously reported. In addition, loss of Smx activity renders the mutant strain sensitive to hydrogen peroxide treatment but relatively unaffected by acid-mediated damage or near-UV irradiation. The smx strain of S. mutans was highly sensitive to the combination of iron and hydrogen peroxide, indicating the likely production of hydroxyl radical by Fenton chemistry with concomitant formation of AP sites that are normally processed by the wild-type allele. Smx activity was sufficiently expressed in E. coli to protect an xth mutant strain from the effects of hydrogen peroxide treatment. The data indicate that S. mutans expresses an inducible, class II-like AP endonuclease, encoded by the smx gene, that exhibits exonucleolytic activity and is regulated as part of the acid-adaptive response of the organism. Smx is likely the primary, if not the sole, AP endonuclease induced during growth at low pH values.
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PMID:Smx nuclease is the major, low-pH-inducible apurinic/apyrimidinic endonuclease in Streptococcus mutans. 1580 17


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