A specific structural interaction of Alzheimer's peptide A beta 1-42 with alpha 1-antichymotrypsin.
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Alzheimer Disease↗
Biomedical subjects
H T Wright
Publications and source records attributed to H T Wright.
Structural basis for serpin inhibitor activity.
The mechanism of formation and the structures of serpin-inhibitor complexes are not completely understood, despite detailed knowledge of the structures of a number of cleaved and uncleaved inhibitor, noninhibitor, and latent serpins. It has been proposed from comparison of inhibitor and noninhibitor serpins in the cleaved and uncleaved forms that insertion of strand s4A into preexisting beta-sheet A is a requirement for serpin inhibitor activity. We have investigated the role of this strand in formation of serpin-proteinase complexes and in serpin inhibitor activity through homology modeling of wild type inhibitor, mutant substrate, and latent serpins, and of putative serpin-proteinase complexes. These models explain the high stability of the complexes and provide an understanding of substrate behavior in serpins with point mutations in s4A and of latency in plasminogen activator inhibitor I.
Amino Acid Sequence↗
Proteolytically cleaved mutant antithrombin-Hamilton has high stability to denaturation characteristic of wild type inhibitor serpins.
The serpin family of proteins consists primarily of proteinase inhibitors which form tight complexes with target proteinases. Inhibitor serpins are cleaved by proteinase and undergo a large conformational change in which the polypeptide segment terminating at the target reactive site, at which cleavage takes place, inserts itself as an additional strand, s4A, in the center of a preexisting beta-sheet. This change in conformation increases the stability towards denaturation of the cleaved serpin relative to the native uncleaved form. Mutant serpins with single amino acid changes in the s4A strand have been identified, and in most cases these are proteinase substrates but not inhibitors. We have measured the stability to denaturation of one of these non-inhibitor substrate mutants, antithrombin-Hamilton, which has an Ala-->Thr change at position P12 in strand s4A. We find that it undergoes the transformation to the more stable form which is observed for inhibitor serpins, from which we conclude that the Ala-->Thr change in antithrombin-Hamilton does not prevent insertion of s4A into beta-sheet A in the cleaved form.
Antithrombin III↗
Diffraction grade crystals of Escherichia coli serine hydroxymethyltransferase.
Diffraction grade crystals of serine hydroxymethyltransferase were obtained after extensive screening of source of enzyme, purification procedures, ligand binding and crystallization conditions. Serine hydroxymethyltransferase purified from Escherichia coli crystallizes in two forms that are suitable for crystal structure determination.
Animals↗
Epidemic measles in the postvaccine era: evaluation of epidemiology, clinical presentation and complications during an urban outbreak.
A total of 440 cases of measles were seen at a single children's hospital during an epidemic in a large urban center. These cases were retrospectively analyzed for demographic characteristics, exposure histories, risk factors for and incidence of complications, outcome and financial consequences. More than 90% of children were < 5 years of age and 56% were < 15 months of age. Ninety-four percent were of Hispanic or African-American ethnic background. A visit to a medical facility was the only source of infection for 83 of the 115 patients for whom exposure histories were available. Four patients with underlying immunodeficiency were among those nosocomially exposed and one died of pulmonary complications. Of the 440 patients 195 (44.3%) required hospitalization for measles complications. The mean age of hospitalized patients, 1.9 +/- 2.4 years, was not different from those not admitted (2.1 +/- 2.5 years; P < 0.25). The most frequent indications for admission were respiratory tract complications (pneumonia and/or croup) seen in 161 patients and dehydration in 25 patients. Fourteen required intensive care and 11 required intubation and mechanical ventilation. Three children died, all of pulmonary involvement. Total hospital and medical charges for care of these patients was more than $1.7 million dollars.
Adolescent↗
Evolution of a family of N-acetylglucosamine binding proteins containing the disulfide-rich domain of wheat germ agglutinin.
A disulfide-rich domain, first identified in wheat germ agglutinin, has now been identified in the amino acid and DNA sequences of a large number of other chitin-binding proteins. This 43-residue domain includes eight disulfide-linked cysteines and has been implicated in the binding of N-acetylglucosamine and its polymers. This study used 12 complementary DNA sequences and 1 amino acid sequence of proteins with one, two, and four copies of this domain to infer a 44-amino acid residue ancestor sequence for this domain, and to derive an evolutionary tree relating these domains in the different proteins. The tree relating these single-domain sequences is divided into two major branches, one consisting of the multidomain dimeric lectins, which we have earlier suggested arose by duplication of a single copy of the disulfide-rich domain, and the other branch consisting of the monomeric chitinases and wound-inducible proteins, which have a single copy of the domain fused to a larger polypeptide. Reference to the three-dimensional structure of WGA and its saccharide complexes shows that the saccharide-binding residues as well as cysteine and glycine residues are conserved among all available sequences. In contrast, many residues at the dimer interface of the domains of WGA are not conserved in those proteins with a single domain, implying that the aggregation state of the domains in these proteins differs from that of the gras lectins. Also, the base compositions of the four-domain and one-domain branches of the tree differ, indicating distinct selective pressures at the level of both protein structure and the gene or its transcript.
Acetylglucosamine↗
Nosocomial measles infection in a pediatric hospital during a community-wide epidemic.
From Jan. 1, 1988, through Dec. 31, 1988, a total of 89 cases of measles were observed at Childrens Hospital of Los Angeles, and 37 patients were admitted to the hospital. Of the 37 patients, six were not initially thought to have measles, which resulted in exposure of 107 patients and 24 personnel. Of the exposed patients, measles developed in four. One nosocomially infected infant died of pneumonia. Another exposed patient was subsequently admitted to another hospital with unrecognized measles, which led to exposure of an additional eight patients. Of seven employees in whom measles developed, two required hospitalization because of pneumonia. Two hundred eleven employee days were lost because of measles exposure or infection. Infection control interventions included prophylaxis of exposed patients, employee education, and measles immunization for susceptible personnel. Of 1103 hospital personnel considered susceptible to measles, 800 received monovalent measles vaccine. No secondary cases of measles occurred in hospital personnel who received appropriate prophylaxis. We conclude that infection control programs aimed at mandating measles immunity in hospital employees at risk should be instituted.
Age Factors↗
Sequence and structure determinants of the nonenzymatic deamidation of asparagine and glutamine residues in proteins.
The rates of deamidation of Asn and Gln residues in peptides and proteins depend upon both the identity of other nearby amino acid residues, some of which can catalyze the deamidation reaction of the Asn and Gln side chains, and upon polypeptide conformation. Proximal amino acids can be contiguous in sequence or brought close to Asn or Gln side chains by higher order structure of the protein. Local polypeptide conformation can stabilize the oxyanion transition state of the deamidation reaction and also enable deamidation through the beta-aspartyl shift mechanism. In this paper, the environments of Asn and Gln residues in known protein structures are examined to determine the configuration and identity of groups which participate in deamidation reactions. Sequence information is also analyzed and shown to support evolutionary selection against the occurrence of certain potentially catalytic amino acids adjacent to Asn and Gln in proteins. This negative selection supports a functional role for deamidation in those non-mutant proteins in which it occurs.
Amino Acid Sequence↗
Imipenem/cilastatin treatment of bacterial meningitis in children.
The safety and efficacy of imipenem/cilastatin were evaluated in 21 children, ages 3 to 48 months, with bacterial meningitis. Eradication of bacteria from the cerebrospinal fluid was demonstrated within 24 hours of antibiotic therapy in all but 2 patients who had Haemophilus influenzae type b meningitis and ultimately achieved bacteriologic cure after 2 to 3 days of imipenem/cilastatin therapy. Cerebrospinal fluid penetrations of imipenem and cilastatin were determined at various times after drug administration with mean cerebrospinal fluid: serum ratios of 14 and 10% for imipenem and cilastatin, respectively. The study was terminated when 7 (33%) patients developed seizure activity after antibiotic therapy was administered. The usefulness of imipenem/cilastatin for the treatment of bacterial meningitis in children may be limited by a possible increased incidence of drug-related seizure activity.
Anti-Bacterial Agents↗
Nonenzymatic deamidation of asparaginyl and glutaminyl residues in proteins.
Some asparagine and glutamine residues in proteins undergo deamidation to aspartate and glutamate with rates that depend upon the sequence and higher-order structure of the protein. Functional groups within the protein can catalyze this reaction, acting as general acids, bases, or stabilizers of the transition state. Information from specific proteins that deamidate and analysis of protein sequence and structure data bases suggest that asparagine and glutamine lability has been a selective pressure in the evolution of protein sequence and folding. Asparagine and glutamine deamidation can affect protein structure and function in natural and engineered mutant sequences, and may play a role in the regulation of protein folding, protein breakdown, and aging.
Amides↗
Crystal structure of plakalbumin, a proteolytically nicked form of ovalbumin. Its relationship to the structure of cleaved alpha-1-proteinase inhibitor.
The crystal structure of plakalbumin, a proteolytically nicked form of ovalbumin, has been determined to a resolution of 2.8 A by the isomorphous replacement method and preliminary refinement. The structure closely resembles that of the cleaved form of alpha-1-proteinase inhibitor, with some important exceptions. The disposition of the new carboxyl chain terminus liberated by proteolysis is different with respect to the central beta-sheet A in the structures of these two molecules. In alpha-1-proteinase inhibitor, the new chain terminus inserts in beta-sheet A to add a middle strand to the sheet. In plakalbumin, this strand remains free near the site at which the cleavage occurs. A structural basis for this difference in behavior is proposed from the structures and sequences of these two molecules and other members of the serpin family. The structures and positions of the putative signal peptide of ovalbumin, the several post-translational modifications, and the relationship of the intron-exon patterns of plakalbumin and alpha-1-proteinase inhibitor to their protein structures are also described.
Amino Acid Sequence↗
Modeling the intact form of the alpha 1-proteinase inhibitor.
The structure of the intact form of the serpin alpha 1-proteinase inhibitor has been modeled based on the assumption that the central strand s4A of the six-stranded beta-sheet A of the cleaved inhibitor is not incorporated into the sheet of intact alpha 1-proteinase inhibitor. This strand was removed from its position in the center of the sheet by suitable rotations about the backbone dihedrals of Lys343 using molecular graphics. The resulting structure was then annealed using molecular dynamics (MD) while applying progressive distance restraints to the reactive peptide bond (Met358-Ser359) for 50 ps. During this time, the disrupted beta-sheet reformed to create a five-stranded beta-sheet with strands 3 and 5 in a parallel arrangement. This change and accompanying structural rearrangements are largely confirmed by the X-ray structure of plakalbumin, whose structure reflects the overall structure of intact serpins. The successful modeling experiment demonstrates the utility of MD for making gross structural predictions based on related structures. The binding loop of the intact form is modeled to allow docking with serine proteinases, in particular thrombin, which most highly constrains the possible conformations of the binding loop.
Models, Chemical↗
Omphalitis in the newborn infant.
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Bacteria, Anaerobic↗
Meningococcal infections.
In Los Angeles, a substantial increase in the number of infections due to Neisseria meningitidis has been noted. More alarming has been an associated mortality rate of 21%. The prompt recognition of meningococcal disease based on a high index of suspicion and the early institution of effective antibiotic treatment are essential for preventing complications and reducing mortality.
Child↗
Crystals of a trypsin-modified alkaline phosphatase. Preliminary crystallographic characterization.
Trypsin-modified alkaline phosphatase from Escherichia coli has been crystallized in a form distinct from the two known crystal forms of the native enzyme. The large well diffracting crystals belong to the orthorhombic space group P2(1)2(1)2(1), possess unit cell dimensions a = 56.0 A, b = 136.0 A, c = 283.9 A with 2 dimers per asymmetric unit, and are suitable for high resolution x-ray crystallographic studies. The observed structural and functional differences between the native and modified molecules are a result of peptide bond cleavage at Arg10-Ala11 with loss of the NH2-terminal decapeptide in both subunits of the dimer.
Alkaline Phosphatase↗
Group A beta-hemolytic streptococci as a cause of bacteremia in children.
The clinical manifestations of patients with group A beta-hemolytic streptococcal (GAS) bacteremia presenting to an urban children's hospital were reviewed. Group A beta-hemolytic streptococci were isolated from blood cultures from 17 children over a three-year period. Systemic illnesses that may have predisposed these children to GAS bacteremia were identified in seven patients: preceding varicella infection (four patients) or malignant neoplasm/immunosuppressive therapy (three patients). Possible sources of GAS included compromised integument (seven patients), the oropharynx (six patients), or the lower respiratory tract (two patients). The clinical manifestations of GAS sepsis included the following: fever (15 patients); arthritis or arthralgias (four patients); cellulitis (three patients); maculopapular eruption (one patient); petechial or pustular exanthems (three patients); osteomyelitis (two patients); cervical adenitis (one patient); empyema (one patient); and meningitis with multiple brain abscesses (one patient). Two patients died of apparent overwhelming GAS sepsis while at home. Group A beta-hemolytic streptococcal bacteremia can present with a wide range of clinical manifestations and cause mild to fulminant disease in children.
Child↗
Haemophilus influenzae type b vaccines: lessons from the past.
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Bacterial Capsules↗
The intersubunit disulfide bridge of ricin is essential for cytotoxicity.
Alkylation of the cysteine residues which link the A and B chains of ricin through a disulfide bridge produces a molecule which still binds to HeLa cells and is toxic toward in vitro ribosome-directed translation, but which has little or no cytotoxicity toward cells in culture. This and similar observations on diphtheria toxin implicate the intersubunit disulfide bridge in the transport of the toxic subunits of these toxins into the cytoplasm.
Alkylation↗