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P Lindley

Publications and source records attributed to P Lindley.

At least 19 recordsLinked to original sources
PubMed1998

Crystal structures of native and recombinant yeast fumarase.

Crystal structures for both native and recombinant forms of yeast fumarase from Saccharomyces cerevisiae have been completed to moderate resolution by two separate laboratories. The recombinant form was obtained by the construction of an expression plasmid for Escherichia coli. Despite a high level of amino acid sequence similarity, purification of the eukaryotic enzyme from the wild-type prokaryotic enzyme was feasible. The crystal structure of the native form, NY-fumarase, encompasses residues R22 through M484, while the recombinant form, RY-fumarase, consists of residues S27 through L485. Both crystal structures lack the N-terminal translocation segment. Each subunit of the homo-tetrameric protein has three domains. The active site is formed by segments from each of three polypeptide chains. The results of these studies on the eukaryotic proteins are unique, since the recombinant form was done in the absence of dicarboxylic acid and has an unoccupied active site. As a comparison, native fumarase was crystallized in the presence of the competitive inhibitor, meso-tartrate. Meso-tartrate occupies a position close to that of the bound citrate molecule found in the active site of the E. coli enzyme. This inhibitor participates in hydrogen bonding to an active-site water molecule. The independent determination of the two structures provides further evidence that an active-site water molecule may play an active role in the fumarase-catalyzed reaction.

Binding Sites↗
PubMed1997

A molecular model for the triplicated A domains of human factor VIII based on the crystal structure of human ceruloplasmin.

The hemophilia A mutation database lists more than 160 missense mutations: each represents a molecular defect in the FVIII molecule, resulting in the X-linked bleeding disorder hemophilia A with a clinical presentation varying from mild to severe. Without a three-dimensional FVIII structure it is in most cases impossible to explain biological dysfunction in terms of the underlying molecular pathology. However, recently the crystal structure of the homologous human plasma copper-binding protein ceruloplasmin (hCp) has been solved, and the A domains of FVIII share approximately 34% sequence identity with hCp. This advance has enabled the building of a molecular model of the A domains of FVIII based on the sequence identity between the two proteins. The model allows exploration of predictions regarding the general features of the FVIII molecule, such as the binding-sites for factor IXa and activated protein C; it has also allowed the mapping of more than 30 selected mutations with known phenotype from the database, and the prediction of hypothetical links to dysfunction in all but a few cases. A computer-generated molecular model such as that reported here cannot substitute for a crystal structure. However, until such a structure for FVIII becomes available, the model represents a significant advance in modeling FVIII; it should prove a useful tool for exploiting the increasing amount of information in the hemophilia A mutation database, and for selecting appropriate targets for investigation of the structure-function relationships via mutagenesis and expression in vitro.

Amino Acid Sequence↗
PubMed1996

The haemophilia A mutation search test and resource site, home page of the factor VIII mutation database: HAMSTeRS.

In order to facilitate easy access to and aid understanding of the causes of haemophilia A at the molecular level we have constructed HAMSTeRS, the third release of the factor VIII mutation database and the first release of this database that may be accessed and interrogated over the internet through a World Wide Web browser. The database also presents a review of the structure and function of factor VIII and the molecular genetics of haemophilia A, a real time update of the biostatistics of each parameter in the database, a molecular model of the A1, A2 and A3 domains of the factor VIII protein (based on the crystal structure of caeruloplasmin) and a bulletin board for discussion of issues in the molecular biology of factor VIII.

Databases, Factual↗
PubMed1994

The structure of avian eye lens delta-crystallin reveals a new fold for a superfamily of oligomeric enzymes.

The crystal structure of turkey delta-crystallin, a principal soluble components of the avian lens, has been determined to a resolution of 2.5 A. It is a tetramer, of 200,000 M(r), with 222 symmetry. The subunit has a new fold composed of three mainly alpha-helical domains. One domain is a bundle of five long helices which forms a 20-helix bundle at the core of the tetramer. delta-crystallin shares approximately 90% sequence identity with the enzyme argininosuccinate lyase (EC 4.3.2.1), indicating that it is an example of a 'hijacked' enzyme. It is also distantly related to the class II fumarases, aspartases, adenylosuccinases and 3-carboxy-cis,cis-muconate lactonising enzyme. The structure reveals a putative active-site cleft which is located on the boundary between three subunits of the tetramer. This is the first three-dimensional structure of a representative of this superfamily of enzymes.

Amino Acid Sequence↗
PubMed1984

The molecular structures and interactions of bovine and human gamma-crystallins.

Knowledge of the three-dimensional structure of bovine gamma II-crystallin has provided the basis for building molecular models using computer graphics of two human gamma-crystallins, the sequences of which have recently been determined. The tertiary structures of these gamma-crystallins are predicted to be highly conserved. They have extensive networks of interacting charges on their surfaces, which may contribute to their thermodynamic stability and partially define the degree of water retention in the lens. The human crystallins appear to be more hydrophobic than the bovine molecule. All have arrangements of cysteine thiols which may be important as electron sinks and reserve redox potential in the normal lens but which may contribute to protein aggregation in cataract.

Amino Acid Sequence↗
PubMed1983

X-ray analysis of the eye lens protein gamma-II crystallin at 1.9 A resolution.

We report the X-ray structure analysis and refinement at 1.9 A resolution of calf gamma-II crystallin, a lens-specific protein. The sequence of Croft (1972) has been modified to give a polypeptide chain of 174 residues (cf. 165). The protein has a symmetrical, hierarchical structure of two globular domains each comprising two similar "Greek key" motifs, consecutive along the polypeptide chain, and related by a pseudo 2-fold axis. The two domains pack together with a single connection and are related by a further pseudo 2-fold axis which bisects the angle between the intra-domain dyads. Forty-two pairs of C alpha positions for the two most similar motifs have root-mean-square separation at best fit of 0.69 A. The N and C-terminal domains gave root-mean-square separation of 0.89 A for 82 pairs of C alpha atoms at best fit. In each domain the two Greek key motifs form a pair of four-stranded antiparallel beta-pleated sheets, each sheet composed of three stands from one motif and one from the other. The sheets pack together in a wedge shape, closed at the top by the loops connecting the third and fourth strands of each motif. The first two strands of each motif form an extended beta-hairpin which is folded on to the beta-sheet. The packing of each motif into the globular domains involves a staggered bilayer of side-chains between each pair of beta-sheets which does not preserve the pseudo 2-fold axes observed in the C alpha position topology. In the core of each domain there are interactions between polarizable aromatic groups and sulphur-containing residues which may contribute to stability and may also serve to protect aromatic side-chains from ultraviolet light damage in the lens. At the surface of the molecule over half the ionic side-chains are closely paired, which probably stabilizes the tertiary fold and may reduce the water bound. Crystal lattice interactions are described which may be similar to those occurring in vivo in the lens between crystallins. Seven cysteine residues have been identified in the structure and these may have a role in the thermodynamic stability of the molecule, its intermolecular interactions under the normal reducing conditions of the lens, and also in the aggregation and cross-linking which occur in some forms of cataract. Three of these residues, Cys18, Cys23 and Cys74, form a cluster in the N-terminal domain.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1981

The molecular structure and stability of the eye lens: x-ray analysis of gamma-crystallin II.

The three-dimensional structure of the eye lens protein, bovine gamma-crystallin II, has been determined at 2.6 A resolution. The protein has a tow domain beta-structure, folded into four remarkably similar 'Greed key' motifs, and shows the highest internal symmetry of any protein studied by X-ray analysis. Although the symmetrical structure seems very stable, the arrangement of the sulphydryl groups would allow intramolecular cross-linking leading to possible destabilization, and intermolecular cross-linking leading to aggregation, both of which may be important to cataract formation.

Amino Acid Sequence↗
PubMed1979

Interviewing skill: the effects of ultra-brief training for general practitioners. A preliminary report.

Concepts of interviewing skill and of appropriate training and evaluation are briefly reviewed. It is hypothesized that if goals and skills relevant to a specific clinical interview can be identified and modelled in advance then even very brief training can improve outcome. An experiment is described in which three randomly selected general practitioners conducted, separately, test interviews with the same role played 'patient'. These interviews were repeated after a 'goal focusing' exercise and again after a modelling and instruction exercise. All interviews were telerecorded and subsequently blindly rated for impact on the 'patient'. The results suggest powerful training effects. The drawbacks of the study, such as lack of controls, are discussed. The similarity of evaluation raters who were 'behaviour' orientated and those who were 'psycho-dynamics' orientated is noted and it is suggested that agreed concepts of effective interviewing may be within reach.

Education, Medical, Continuing↗
PubMed1979

Nurse therapists in psychiatry: developments, controversies and implications.

This paper concerns a new clinical role for psychiatric nurses--as case managers for selected adult neurotics with behaviour problems. The role involves unusual autonomy. The selection and training procedures are unusually rigorous and focus on general case-management as much as behavioural skills. The number of service posts offered these therapists is rising. These developments have wide implications for other personnel, particularly in respect of authority and responsibility boundaries, selection and training procedures, and team structure.

Adult↗
PubMed1977

Treatment of obsessive-compulsive neurosis with history of childhood autism.

A young man was followed-up over three years who had severe obsessive-compulsive rituals and ruminations, interpersonal deficits, complicating depression and a history of childhood autism. Intensive behavioural treatment was given in an operant framework, with exposure in vivo, modelling, response prevention and social skills training. Compulsive rituals improved markedly and lastingly, but ruminations and social defects persisted. When intercurrent depression occurred dothiepin facilitated behavioural treatment. Adjustment remained fragile. Minimum maintenance treatment in the community could not be adequately arranged, so that gains made in hospital were partly lost at follow-up, despite continuing improvement in rituals.

Adult↗
PubMed1977

Social skills training of out-patient groups. A controlled study of rehearsal and homework.

Fifty-one out-patients with social skills deficits (two-thirds men) completed ten weekly sessions of 75-minute group treatment; 44 were followed up for a mean of 16 months. Random assignment was to one of three conditions: (I) Cohesive group discussion; (2) Modelling and role-rehearsal; or (3) Modelling and role-rehearsal + daily social homework. All three treatment conditions produced significant but incomplete improvement at the end of treatment and follow-up. The two role-rehearsal conditions were significantly superior to group discussion on several measures. Patients who completed daily social homework assignments did significantly better than patients who completed control homework. Alcohol and drug abuse patients usually dropped out. Schizophrenic patients in remission had lost their improvement at follow-up. Patients with other diagnoses retained their gains to 16-month follow-up.

Ambulatory Care↗
PubMed1976

Suicide.

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Humans↗