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1. Freezing and folding behavior in simple off-lattice heteropolymers

Author

Magee, J. E., Warwicker, J., and Lue, L.

Subjects
Condensed Matter - Soft Condensed Matter, Physics - Biological Physics, Quantitative Biology - Biomolecules
Abstract

We have performed parallel tempering Monte Carlo simulations using a simple continuum heteropolymer model for proteins. All ten heteropolymer sequences which we have studied have shown first-order transitions at low temperature to ordered states dominated by single chain conformations. These results are in contrast with the theoretical predictions of the random energy model for heteropolymers, from which we would expect continuous transitions to glassy behavior at low temperatures., Comment: 14 pages, 7 figures, submitted to J. Chem. Phys

Published
2004
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3. MerTK kinase domain in complex with a bisaminopyrimidine inhibitor

Author

Pflug, A., primary, Nissink, J.W.M., additional, Blackett, C., additional, Goldberg, K., additional, Hennessy, E.J., additional, Hardaker, E., additional, McCoull, W., additional, McMurray, L., additional, Collingwood, O., additional, Overman, R., additional, Preston, M., additional, Rawlins, P., additional, Rivers, E., additional, Schimpl, M., additional, Smith, P., additional, Underwood, E., additional, Truman, C., additional, Warwicker, J., additional, Winter, J., additional, and Woodcock, S., additional

Published
2021
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4. MerTK kinase domain in complex with a type 2 inhibitor

Author

Schimpl, M., primary, Nissink, J.W.M., additional, Blackett, C., additional, Goldberg, K., additional, Hennessy, E.J., additional, Hardaker, E., additional, McCoull, W., additional, McMurray, L., additional, Collingwood, O., additional, Overman, R., additional, Pflug, A., additional, Preston, M., additional, Rawlins, P., additional, Rivers, E., additional, Smith, P., additional, Underwood, E., additional, Truman, C., additional, Warwicker, J., additional, Winter, J., additional, and Woodcock, S., additional

Published
2021
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5. MerTK kinase domain in complex with NPS-1034

Author

Schimpl, M., primary, Nissink, J.W.M., additional, Blackett, C., additional, Goldberg, K., additional, Hennessy, E.J., additional, Hardaker, E., additional, McCoull, W., additional, McMurray, L., additional, Collingwood, O., additional, Overman, R., additional, Pflug, A., additional, Preston, M., additional, Rawlins, P., additional, Rivers, E., additional, Smith, P., additional, Underwood, E., additional, Truman, C., additional, Warwicker, J., additional, Winter, J., additional, and Woodcock, S., additional

Published
2021
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6. MerTK kinase domain in complex with quinazoline-based inhbitor

Author

Schimpl, M., primary, Nissink, J.W.M., additional, Blackett, C., additional, Goldberg, K., additional, Hennessy, E.J., additional, Hardaker, E., additional, McCoull, W., additional, McMurray, L., additional, Collingwood, O., additional, Overman, R., additional, Pflug, A., additional, Preston, M., additional, Rawlins, P., additional, Rivers, E., additional, Smith, P., additional, Underwood, E., additional, Truman, C., additional, Warwicker, J., additional, Winter, J., additional, and Woodcock, S., additional

Published
2021
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7. MerTK kinase domain with type 1.5 inhibitor from a DNA-encoded library

Author

Schimpl, M., primary, Nissink, J.W.M., additional, Blackett, C., additional, Goldberg, K., additional, Hennessy, E.J., additional, Hardaker, E., additional, McCoull, W., additional, McMurray, L., additional, Collingwood, O., additional, Overman, R., additional, Pflug, A., additional, Preston, M., additional, Rawlins, P., additional, Rivers, E., additional, Smith, P., additional, Underwood, E., additional, Truman, C., additional, Warwicker, J., additional, Winter, J., additional, and Woodcock, S., additional

Published
2021
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8. MerTK kinase domain in complex with purine inhibitor

Author

Schimpl, M., primary, Nissink, J.W.M., additional, Blackett, C., additional, Clarke, M., additional, Disch, J., additional, Goldberg, K., additional, Guilinger, J., additional, Hennessy, E.J., additional, Jetson, R., additional, Ginkunja, D., additional, Hardaker, E., additional, Keefe, A., additional, McCoull, W., additional, McMurray, L., additional, Collingwood, O., additional, Overman, R., additional, Pflug, A., additional, Preston, M., additional, Rawlins, P., additional, Rivers, E., additional, Smith, P., additional, Underwood, E., additional, Truman, C., additional, Warwicker, J., additional, Winter, J., additional, Woodcock, S., additional, and Zhang, Y., additional

Published
2021
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9. MerTK kinase domain with type 3 inhibitor from a DNA-encoded library

Author

Pflug, A., primary, Nissink, J.W.M., additional, Blackett, C., additional, Goldberg, K., additional, Hennessy, E.J., additional, Hardaker, E., additional, McCoull, W., additional, McMurray, L., additional, Collingwood, O., additional, Overman, R., additional, Preston, M., additional, Rawlins, P., additional, Rivers, E., additional, Schimpl, M., additional, Smith, P., additional, Underwood, E., additional, Truman, C., additional, Warwicker, J., additional, Winter, J., additional, and Woodcock, S., additional

Published
2021
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13. Apo crystal structure of the MerTK kinase domain

Author

Pflug, A., primary, Schimpl, M., additional, McCoull, W., additional, Nissink, J.W.M., additional, Overman, R.C., additional, Rawlins, P.B., additional, Truman, C., additional, Underwood, E., additional, Warwicker, J., additional, and Winter-Holt, J., additional

Published
2020
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18. Structure and mechanism of the bifunctional CinA enzyme from Thermus thermophilus

Author

Karuppiah, V, Thistlethwaite, A, Dajani, R, Warwicker, J, and Derrick, JP.

Subjects
X-ray Crystallography, DNA Transformation, Enzyme Catalysis, ADP-ribose Pyrophosphatase, Hydrolase, COG1058 Domain, Nicotinamide Mononucleotide Deamidase, Nicotinamide Adenine Dinucleotide (NAD)
Abstract

CinA is a widely distributed protein in Gram-positive and Gram-negative bacteria. It is associated with natural competence and is proposed to have a function as an enzyme participating in the pyridine nucleotide cycle, which recycles products formed by non-redox uses of NAD. Here we report the determination of the crystal structure of CinA from Thermus thermophilus, in complex with several ligands. CinA was shown to have both nicotinamide mononucleotide (NMN) deamidase and ADP-ribose pyrophosphatase activities. The crystal structure shows an unusual asymmetric dimer, with three domains for each chain; the C-terminal domain harbours the NMN deamidase activity and the structure of a complex with the product nicotinate mononucleotide suggests a mechanism for deamidation. The N-terminal domain belongs to the COG1058 family and is associated with the ADP-ribose pyrophosphatase activity. The asymmetry in the CinA dimer arises from two alternative orientations of the COG1058 domains, only one of which forms a contact with the KH-type domain from the other chain, effectively closing the active site into, we propose, a catalytically competent state. Structures of complexes with Mg2+/ADP-ribose, Mg2+/ATP and Mg2+/AMP suggest a mechanism for the ADP-ribose pyrophosphatase reaction which involves a rotation of the COG1058 domain dimer as part of the reaction cycle, so that each active site oscillates between open and closed forms, thus promoting catalysis.

Published
2014
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22. The transcriptional regulator CprK detects chlorination by combining direct and indirect readout mechanisms

Author

Kemp, LR, Dunstan, MS, Fisher, K, Warwicker, J, Leys, D, Kemp, LR, Dunstan, MS, Fisher, K, Warwicker, J, and Leys, D

Abstract

The transcriptional regulator CprK controls the expression of the reductive dehalogenase CprA in organohalide-respiring bacteria. Desulfitobacterium hafniense CprA catalyses the reductive dechlorination of the terminal electron acceptor o-chlorophenol acetic acid, generating the phenol acetic acid product. It has been shown that CprK has ability to distinguish between the chlorinated CprA substrate and the de-halogenated end product, with an estimated an estimated 10(4)-fold difference in affinity. Using a green fluorescent protein GFPUV-based transcriptional reporter system, we establish that CprK can sense o-chlorophenol acetic acid at the nanomolar level, whereas phenol acetic acid leads to transcriptional activation only when approaching micromolar levels. A structure-activity relationship study, using a range of o-chlorophenol acetic-acid-related compounds and key CprK mutants, combined with pKa calculations on the effector binding site, suggests that the sensitive detection of chlorination is achieved through a combination of direct and indirect readout mechanisms. Both the physical presence of the bulky chloride substituent as well as the accompanying electronic effects lowering the inherent phenol pKa are required for high affinity. Indeed, transcriptional activation by CprK appears strictly dependent on establishing a phenolate-K133 salt bridge interaction, rather than on the presence of a halogen atom per se. As K133 is strictly conserved within the CprK family, our data suggest that physiological function and future applications in biosensing are probably restricted to phenolic compounds.

Published
2013

23. Visualization of poly(ADP-ribose) bound to PARG reveals inherent balance between exo- and endo-glycohydrolase activities

Author

Barkauskaite, E, Brassington, A, Tan, ES, Warwicker, J, Dunstan, MS, Banos, B, Lafite, P, Ahel, M, Mitchison, TJ, Ahel, I, Leys, D, Barkauskaite, E, Brassington, A, Tan, ES, Warwicker, J, Dunstan, MS, Banos, B, Lafite, P, Ahel, M, Mitchison, TJ, Ahel, I, and Leys, D

Abstract

Poly-ADP-ribosylation is a post-translational modification that regulates processes involved in genome stability. Breakdown of the poly(ADP-ribose) (PAR) polymer is catalysed by poly(ADP-ribose) glycohydrolase (PARG), whose endo-glycohydrolase activity generates PAR fragments. Here we present the crystal structure of PARG incorporating the PAR substrate. The two terminal ADP-ribose units of the polymeric substrate are bound in exo-mode. Biochemical and modelling studies reveal that PARG acts predominantly as an exo-glycohydrolase. This preference is linked to Phe902 (human numbering), which is responsible for low-affinity binding of the substrate in endo-mode. Our data reveal the mechanism of poly-ADP-ribosylation reversal, with ADP-ribose as the dominant product, and suggest that the release of apoptotic PAR fragments occurs at unusual PAR/PARG ratios.

Published
2013

24. Polyunsaturated fatty acids inhibit Kv1.4 by interacting with positively charged extracellular pore residues.

Author

Farag, N. E., Jeong, D., Claydon, T., Warwicker, J., and Boyett, M. R.

Subjects
UNSATURATED fatty acids, ACIDOSIS, ACID-base imbalances, VOLTAGE-clamp techniques (Electrophysiology), MICROBIAL inactivation
Abstract

Polyunsaturated fatty acids (PUFAs) modulate voltage-gated K+ channel inactivation by an unknown site and mechanism. The effects of ω-6 and ω-3 PUFAs were investigated on the heterologously expressed Kv1.4 channel. PUFAs inhibited wild-type Kv1.4 during repetitive pulsing as a result of slowing of recovery from inactivation. In a mutant Kv1.4 channel lacking N-type inactivation, PUFAs reversibly enhanced C-type inactivation (Kd, 15-43 µM). C-type inactivation was affected by extracellular H+ and K+ as well as PUFAs and there was an interaction among the three: the effect of PUFAs was reversed during acidosis and abolished on raising K+. Replacement of two positively charged residues in the extracellular pore (H508 and K532) abolished the effects of the PUFAs (and extracellular H+ and K+) on C-type inactivation but had no effect on the lipoelectric modulation of voltage sensor activation, suggesting two separable interaction sites/mechanisms of action of PUFAs. Charge calculations suggest that the acidic head group of the PUFAs raises the pKa of H508 and this reduces the K+ occupancy of the selectivity filter, stabilizing the C-type inactivated state. [ABSTRACT FROM AUTHOR]

Published
2016
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29. Calculation of cys 30 Delta pK(a)'s and oxidising power for DsbA mutants

Author

Warwicker, J., Gane, Paul J., Warwicker, J., and Gane, Paul J.

Abstract

DsbA possesses a redox active disulphide, with the equilibrium strongly shifted towards the reduced form as compared to its structural homologue, thioredoxin. It is widely believed that the two amino acids that separate the active site cysteines play a crucial role in determining oxidising power within the thioredoxin family. Data concerning redox and pg, properties for DsbA mutants in this region are available. Electrostatics calculations show reasonable agreement with the experimental data, and support the suggestion that amino acids outside of the CXXC active site sequence are as important in determining oxidising power within the thioredoxin family as are those within it.

Published
1996

30. A Moecular-model for the Redox Potential Differenc Between Thioredoxin and DSBA, Based on Electostatics Calculations

Author

Gane, Paul J., Freedman, Robert B., Warwicker, J., Gane, Paul J., Freedman, Robert B., and Warwicker, J.

Abstract

The disulphide active sites of thioredoxin and DsbA are known to possess a high degree of structural homology: However, DsbA is a much stronger oxidant than thioredoxin. The redox potential difference between DsbA and thioredoxin has been measured to be 160 mV, equivalent to a shift of 15.4 kJ/mol in the reduced/oxidised equilibrium. Electrostatics calculations have been used to study the relative stabilities of the reduced forms of the two proteins. Model calculations suggest that much of the redox potential difference between DsbA and thioredoxin arises form altered stabilisation of the exposed and ionised thiolates of the reduced forms, supporting suggestions previously made on the basis of experimental studies. The calculations have been used to construct a molecular model for the difference in thiolate stabilisation. Although specific interactions, such as thiolate-NH 35 (thioredoxin)/33 (DsbA), provide substantial stabilisation in each reduced protein, the difference between thioredoxin and DsbA is predicted to reside in several side-chain and main-chain groups acting in concert. Residues H32 and Q97 in DsbA are predicted to contribute, along with substantial regions of the polypeptide backbone in the protein domain which is common to DsbA and thioredoxin. Increased thiolate stabilisation by the peptide dipoles is suggested to arise from altered main-chain disposition, and the effect of the additional protein domain of DsbA on the electric field. Peptide dipoles in a region of about 20 residues close to the active site disulphide are predicted to contribute significantly to the redox potential difference.

Published
1995

33. Specific Ion and Buffer Effects on Protein–Protein Interactions of a Monoclonal Antibody

Author

Roberts, D., Keeling, R., Tracka, M., van der Walle, C. F., Uddin, S., Warwicker, J., and Curtis, R.

Abstract

Better predictive ability of salt and buffer effects on protein–protein interactions requires separating out contributions due to ionic screening, protein charge neutralization by ion binding, and salting-in(out) behavior. We have carried out a systematic study by measuring protein–protein interactions for a monoclonal antibody over an ionic strength range of 25 to 525 mM at 4 pH values (5, 6.5, 8, and 9) in solutions containing sodium chloride, calcium chloride, sodium sulfate, or sodium thiocyante. The salt ions are chosen so as to represent a range of affinities for protein charged and noncharged groups. The results are compared to effects of various buffers including acetate, citrate, phosphate, histidine, succinate, or tris. In low ionic strength solutions, anion binding affinity is reflected by the ability to reduce protein–protein repulsion, which follows the order thiocyanate > sulfate > chloride. The sulfate specific effect is screened at the same ionic strength required to screen the pH dependence of protein–protein interactions indicating sulfate binding only neutralizes protein charged groups. Thiocyanate specific effects occur over a larger ionic strength range reflecting adsorption to charged and noncharged regions of the protein. The latter leads to salting-in behavior and, at low pH, a nonmonotonic interaction profile with respect to sodium thiocyanate concentration. The effects of thiocyanate can not be rationalized in terms of only neutralizing double layer forces indicating the presence of an additional short-ranged protein–protein attraction at moderate ionic strength. Conversely, buffer specific effects can be explained through a charge neutralization mechanism, where buffers with greater valency are more effective at reducing double layer forces at low pH. Citrate binding at pH 6.5 leads to protein charge inversion and the formation of attractive electrostatic interactions. Throughout the report, we highlight similarities in the measured protein–protein interaction profiles with previous studies of globular proteins and of antibodies providing evidence that the behavior will be common to other protein systems.

Published
2015
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47. 6-THE EFFECT OF ALKALINE AND ACID SWELLING AGENTS ON THE MECHANICAL PROPERTIES OF COTTON FIBRES.

Author

WARWICKER, J. O. and HALLAM, PATRICIA

Subjects
COTTON, TEXTILE fibers, TEXTILES, STRAINS & stresses (Mechanics), SODIUM hydroxide, PERCHLORIC acid, SULFURIC acid, PHOSPHORIC acid, NITRIC acid, TEXTILE industry
Abstract

study of the changes in mechanical properties of cotton brought about by sodium hydroxide, an iron tartrate complex in caustic soda (EWNN), cuprammonium hydroxide, and sulphuric, phosphoric, nitric, and perchloric acids has been made. Instead of choosing the normal mercerizing conditions with sodium hydroxide, different temperatures of treatment and of washing were studied to see what effect the condition had on the subsequent mechanical properties of the fibres. The variable studied with the other reagents was that of concentration, so that a distinction between interfibrillar and intrafibrillar swelling could be made. The main effect of swelling is to alter the extensibility of the fibre, and this has been analysed at different stages of loading up to break. [ABSTRACT FROM AUTHOR]

Published
1970
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48. 22 -- AN X-RAY STUDY OF THE SORPTION OF WATER BY THE SILK FIBROIN OF BOMBYX MORI.

Author

Warwicker, J. O.

Abstract

The article cites a study which examines the absorption of water by the silk fibroin of Bombyx mori. The aim of the study was to clarify the uncertainties of the evidence provided by several researchers regarding the effect of drying on the lattice constants of silk fibroin. It uses a 25 milligram bundle of parallel 1 inch lengths of degummed silk fibroin from Bombyx mori with piece of copper wire inserted at the center and its ends. Another experiments were fulfilled with degummed silk fibroin to determine the time needed to reach the bone-dry state. After several investigations, the researchers concluded that no change could be observed in the lattice dimensions of fibroin after drying over phosphorus pentoxide.

Published
1960
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