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Your search keyword '"Whisstock, James C"' showing total 10 results
Start Over Author "Whisstock, James C" Journal proceedings of the national academy of sciences of the united states of america
10 results on '"Whisstock, James C"'

5. Structure of the Plasmodium falciparum M17 Aminopeptidase and Significance for the Design of Drugs Targeting the Neutral Exopeptidases

Author

McGowan, Sheena, Oellig, Christine A., Birru, Woldeamanuel A., Caradoc-Davies, Tom T., Stack, Colin M., Lowther, Jonathan, Skinner-Adams, Tina, Mucha, Artur, Kafarski, Pawel, Grembecka, Jolanta, Trenholme, Katharine R., Buckle, Ashley M., Gardiner, Donald L., Dalton, John P., Whisstock, James C., and Stroud, Robert M.

Published
2010
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9. Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase.

Author

McGorrin, Sheena, Porter, Corriene J., Lowther, Jonathan, Stack, Colin M., Golding, Sarah J., Skinner-Adams, Tina S., Trenholme, Katharine R., Teuscher, Franka, Donnelly, Sheila M., Grembecka, Jolanta, Mucha, Artur, Kafarski, Pawel, DeGoria, Ross, Buckle, Ashley M., Gardiner, Donald L., Whisstock, James C., and Dalton, John P.

Subjects
DRUG development, TARGETED drug delivery, ANTINEOPLASTIC agents, AMINOPEPTIDASES, PLASMODIUM falciparum, MALARIA, PARASITES, HEMOGLOBIN polymorphisms
Abstract

Plasmodium falciparum parasites are responsible for the major global disease malaria, which results in >2 million deaths each year. With the rise of drug-resistant malarial parasites, novel drug targets and lead compounds are urgently required for the development of new therapeutic strategies. Here, we address this important problem by targeting the malarial neutral aminopeptidases that are involved in the terminal stages of hemoglobin digestion and essential for the provision of amino acids used for parasite growth and development within the erythrocyte. We characterize the structure and substrate specificity of one such aminopeptidase, PfA-M1, a validated drug target. The X-ray crystal structure of PfA-M1. alone and in complex with the generic inhibitor, bestatin, and a phosphinate dipeptide analogue with potent in vitro and in vivo antimalarial activity. hPheP[CH2]Phe, reveals features within the protease active site that are critical to its function as an aminopeptidase and can be exploited for drug development. These results set the groundwork for the development of antimalarial therapeutics that target the neutral aminopeptidases of the parasite. [ABSTRACT FROM AUTHOR]

Published
2009
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10. Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1.

Author

Li SH, Reinke AA, Sanders KL, Emal CD, Whisstock JC, Stuckey JA, and Lawrence DA

Subjects
Allosteric Regulation, Crystallography, X-Ray, Humans, Plasminogen Activator Inhibitor 1 genetics, Plasminogen Activator Inhibitor 1 metabolism, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, Structure-Activity Relationship, Vitronectin chemistry, Vitronectin genetics, Vitronectin metabolism, Plasminogen Activator Inhibitor 1 chemistry
Abstract

Plasminogen activator inhibitor type-1 (PAI-1) is a member of the serine protease inhibitor (serpin) family. Excessive PAI-1 activity is associated with human disease, making it an attractive pharmaceutical target. However, like other serpins, PAI-1 has a labile structure, making it a difficult target for the development of small molecule inhibitors, and to date, there are no US Food and Drug Administration-approved small molecule inactivators of any serpins. Here we describe the mechanistic and structural characterization of a high affinity inactivator of PAI-1. This molecule binds to PAI-1 reversibly and acts through an allosteric mechanism that inhibits PAI-1 binding to proteases and to its cofactor vitronectin. The binding site is identified by X-ray crystallography and mutagenesis as a pocket at the interface of β-sheets B and C and α-helix H. A similar pocket is present on other serpins, suggesting that this site could be a common target in this structurally conserved protein family.

Published
2013
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