Protein antigenic determinants have been classified as continuous or discontinuous. The continuous determinants are composed of residues which are local in the polypeptide sequence, while discontinuous determinants consist of residues from different parts of the sequence, brought together by the folding of the protein to its native structure. Searches made for protein determinants using peptide fragments which compete with protein-antibody complex formation, or peptides that can be used to raise antibodies which crossreact with the native protein, are limited to the simulation of continuous determinants. However, recent experiments suggest that most determinants are discontinuous. We now show, by consideration of protein surfaces, that if the recognition zone between a protein and antibody has the same dimensions as those found for the lysozyme-antibody complex, none of the protein's surface will be 'continuous'. We suggest that all determinants are discontinuous to some extent, and that crossreacting peptides mimic only the 'primary' interaction site. In addition, we show that the parts of a protein's surface which are most continuous fall predominantly in the loops and/or protruding regions. This explains why quantities such as hydrophilicity, accessibility, mobility and protrusion can be used to predict which parts of a polypeptide provide the 'best' antigenic peptides.
The alpha-helix defined in 1951 by Pauling et al. on the basis of model building and X-ray fibre diffraction data has 3.65 residues per turn (n) achieved with planar peptides, torsion angles of phi = -48 degrees and psi = -57 degrees and hydrogen bonds which are close to linear. Although X-ray analyses of proteins have confirmed the general correctness of the model for the helix, recent high resolution (1.7-1.0 A) diffraction studies have shown that the parameters described by Pauling et al. and later by Perutz and Arnott and Wonacott are not a good description of the alpha-helices in globular proteins, where the mean values of phi, psi are usually close to -63 degrees, -42 degrees. Here we show that these values arise as a mean of two significantly different classes in amphipathic helices depending on whether the peptide carbonyl oxygen is hydrogen bonded to a solvent or polar side-chain atom. The hydrogen bonds made by the hydrophilic carbonyls to the NH groups within helices are longer and less linear than those involving hydrophobic carbonyls. We also show that these effects are associated with a significant curvature of helices in globular proteins. For example, the alpha-helix in avian pancreatic peptide (aPP) has a radius of curvature of approximately 70 A. These results are of significance in the packing of helices in fibrous and globular proteins, in the calculation of their dipole moments, solvent accessibilities and internal energies, and in the theoretical estimation of spectroscopic properties such as circular dichroism and Raman scattering.
SynopsisThe distributions of charged groups in 32 proteins of known three-dimensional structure have been analyzed to determine how regularly the groups are spread over the molecule's surfaces, and to identify and to study those proteins where charge asymmetry would seem important for their function. The distributions have been analyzed in terms of charge "polarity," surface "charge density," and electric dipole moments. More detailed studies of the distributions for individual proteins are made using map projections specifically developed for this purpose. In the light of the results obtained we discuss the role of charged groups in relation to protein function.
(Rcceiwd bcbrtiat-! 27. 19x4) ~ L J B 83 0215 Pancreatic polypeptide has been extracted and sequenced from a wide range of species. The 36-residue polypeptides have some hormonal characteristics, and show a high degree of sequence homology. Two recently isolated polypeptides, from porcine gut and brain, also show a high degree of sequence homology with the pancreatic polypeptides. It was proposed that these polypeptides were members of a related family.The X-ray determined structure of one member of the family, turkey pancreatic polypeptide, is known to high resolution, but there is no structural information for the others. Studies designed to give an insight into the tertiary structure of these related molecules have been carried out, including model building using interactive computer graphics, circular dichroic spectroscopy and secondary structure prediction using a variety of algorithms.The results indicate that a compact globular conformation, similar to that observed in turkey pancreatic polypeptide may be adopted by all molecules and that this may be more highly conserved than the individual amino acid sequences.Since the first identification of pancreatic polypeptide (PP) in the chicken pancreas [l], homologous peptides have been isolated from the alligator (Kimmel, unpublished results), the turkey [2], goose (Shen et al., unpublished results), ox, pig, sheep, dog and human [3]. These 36-residue polypeptides share a feature common to many gastroenteric hormones, a blocked. amidated carboxy terminus. Tatemoto and Mutt [4] used this feature to isolate possible hormonal peptides in tissue extracts and isolated, amongst others, two peptides, PYY from pig intestine [5] and NPY from pig brain tissue [6]. They showed that these polypeptides have considerable homology with the pancreatic polypeptides and proposed that PP, NPY and PYY form a newly recognised hormone family (see Table 1).The structure of one member of this family, turkey pancreatic polypeptide, has been determined by X-ray crystallography [2, 7, 81 and the analysis recently extended to very high resolution, d,,, = 98pm [9-111. The turkey PP protomer comprises of two segments of secondary structure: a polyproline type-I1 helix (residues 1-8) and an a-helix (residues 14-32). These helices, joined by a type-I1 fl-turn, interact via hydrophobic contacts to produce a compact and stable tertiary fold. The C-terminal region, residues 33 -36, extend away from the body of the molecule and display some flexibility in the crystal lattice. Further hydrophobic interactions are achieved by the formation of dimers in which a cage of aromatic residues, related by the crystallographic diad axis, is formed. In the crystal the dimers form extended oligomeric arrays via the coordination of a zinc ion. The zinc coordination involves His-34 Nt: of one, Asp-23 of another and the glycine nitrogen and carbonyl oxygen of a third dimer. The penta-,4hhrericr/ions. PP, pancreatic polypeptide; NPY, pig neuropolypcptide; PYY, pig intestinal polypeptide. coordinated site is c...
Aims and objectivesThe study aimed to evaluate the causes of prevented dispensing incidents reported by hospitals using the critical incident technique developed by key-informant interviews, focus group and observation. Setting All Welsh NHS hospitals (n = 20) were invited to participate in the study. Sixteen hospitals agreed to take part; 10 hospitals reported incidents, four hospitals did not report any incidents and two hospitals withdrew from the study. Method In June 2005 three key-informant interviews and a focus group were conducted to determine dispensary workflow, which was then validated by a piloted non-participant observational study at three Welsh hospitals. Self-reported critical incident forms were then developed to collect dispensing-incident data involving drugs at high risk of dispensing incidents. Sixteen Welsh hospitals participated in the 4-month study (January-August 2006). Key findings Dispensary workflow encompassed the following events: prescription receipt, validating patient information, log of prescription, technical check, clinical check, label generation, stock selection, medicines assembly, product labelling, completion of registers, self-checking/endorsing and final accuracy check. Twenty-four incidents were reported by 10 hospitals involving paediatrics (n = 9, 38%), morphine sulphate (n = 5, 21%), insulin (n = 5, 21%), angiotensin-converting enzyme inhibitors (n = 3, 13%) and nifedipine (n = 2, 8%). Incidents commonly occurred at label generation (n = 9, 43%) and stock selection (n = 9, 43%), caused by error-producing conditions, active and latent failures. Active failures involved dispensing the wrong quantity of medication, interchanging different formulations, and computer and stock-selection errors. Error-producing conditions were reported as high workload, complex prescriptions and interruptions. Latent conditions were inadequate staffing/ skill mix, unclear drug computer selection lists and the storage of drugs on dispensary shelves. Conclusion The critical incident technique provided an in-depth understanding of the causes of dispensing incidents. Dispensing incidents arose because of organisational pathologies, error producing conditions and active failures such as inadequate staffing, high workload, interruptions, and computer and drug-selection errors.Patient safety is of major importance to the pharmacy profession and central to this is the minimisation of dispensing incidents. Unprevented dispensing incidents, detected and reported after the medication has left the pharmacy, occur relatively infrequently at a rate of 16-18 per 100000 items dispensed in UK hospitals. [1][2][3][4] In contrast, prevented dispensing incidents identified during the dispensing process before medication has left the pharmacy occur more frequently, at a rate of 0.94-2.1% in UK hospitals. 1,5,6 Despite the low incidence, dispensing incidents, if undetected, can cause serious patient harm, morbidity and occasionally death. 7-9 Thus it is imperative that the dispensing incidents are reviewed so ...
We have combined new radial velocities of both components of Capella, obtained at McDonald and Kitt Peak, with those recently published by Batten et al. (1991, PASP, 103, 623), and with interferometric observations, mainly from the Second CHARA Catalog, to derive a new three-dimensional orbit of the Capella system. Our results agree well with those of Hartkopf (1989, AJ, 98, 2275), as well as with those of Batten et al., and yield masses accurate to ±3%. The cooler component, which is the fainter star visually but the more luminous one bolometrically, is the more massive. The mass ratio differs from unity by more than four times its uncertainty, and this lends strong support to the hypothesis that the cool component has begun to consume its core helium. If so, it may be possible to reconcile, qualitatively at least, the orbit's circularity and the stars' rotational velocities with theories of synchronization and circularization, such as that of the Tassouls (1992, ApJ, 395, 259)
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