This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Diabetes-associated hyperglycemia is the underlying cause of all of the chronic complications arising from a prolonged diabetic condition. The enzyme phosphoenolpyruvate carboxykinase (PEPCK) plays a key role in the elevated blood glucose levels observed during diabetes-associated hyperglycemia. Our studies focus on understanding how PEPCK catalyzes its biological reaction and how it leads to the development of effective inhibitors of this enzyme as potent anti-hyperglycemic agents. Our application's long-term goals are to understand the role that the inherent dynamic properties of protein catalysts play in the process of enzyme mediated catalysis. The results of these studies will have broad reaching implications in the ability to design novel protein based catalysts, as well as advance our ability to design potent and selective inhibitors of biologically important enzymes in the treatment of disease. By utilizing the enzyme phosphoenolpyruvate carboxykinase our studies will lead directly to the development of selective inhibitors of this enzyme to treat diabetes-associated hyperglycemia. To achieve these goals, we will combine the strengths of x-ray crystallography and NMR to characterize not only the conformational changes that occur during catalysis, but also the time scale in which these motions occur. By correlating these structural and dynamics studies with the ability of the enzyme to carry out catalysis in both the wild-type enzyme and in mutants engineered to upset the dynamic processes, we will achieve a more thorough understanding of the particular roles that these dynamic changes play in the catalytic cycle.
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| Jeanne Dit Fouque, Kevin; Garabedian, Alyssa; Porter, Jacob et al. (2017) Fast and Effective Ion Mobility-Mass Spectrometry Separation of d-Amino-Acid-Containing Peptides. Anal Chem 89:11787-11794 |
| Alaofi, Ahmed; Farokhi, Elinaz; Prasasty, Vivitri D et al. (2017) Probing the interaction between cHAVc3 peptide and the EC1 domain of E-cadherin using NMR and molecular dynamics simulations. J Biomol Struct Dyn 35:92-104 |
| Pang, Xiao-Yan; Wang, Suya; Jurczak, Michael J et al. (2017) Retinol saturase modulates lipid metabolism and the production of reactive oxygen species. Arch Biochem Biophys 633:93-102 |
| McNiff, Michaela L; Chadwick, Jennifer S (2017) Metal-bound claMP Tag inhibits proteolytic cleavage. Protein Eng Des Sel 30:467-475 |
| Johnson, Troy A; Mcleod, Matthew J; Holyoak, Todd (2016) Utilization of Substrate Intrinsic Binding Energy for Conformational Change and Catalytic Function in Phosphoenolpyruvate Carboxykinase. Biochemistry 55:575-87 |
| Tucker, Jenifer K; McNiff, Michaela L; Ulapane, Sasanka B et al. (2016) Mechanistic investigations of matrix metalloproteinase-8 inhibition by metal abstraction peptide. Biointerphases 11:021006 |
| Yadav, Rahul; Vattepu, Ravi; Beck, Moriah R (2016) Phosphoinositide Binding Inhibits Actin Crosslinking and Polymerization by Palladin. J Mol Biol 428:4031-4047 |
| Gurung, Ritu; Yadav, Rahul; Brungardt, Joseph G et al. (2016) Actin polymerization is stimulated by actin cross-linking protein palladin. Biochem J 473:383-96 |
| Budiardjo, S Jimmy; Licknack, Timothy J; Cory, Michael B et al. (2016) Full and Partial Agonism of a Designed Enzyme Switch. ACS Synth Biol 5:1475-1484 |
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