STRUCTURAL DETERMINANTS FOR THE ALLOSTERIC REGULATION OF MAMMALIAN PEPCK

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Phosphoenolpyruvate carboxykinase (PEPCK) is a key enzyme in gluconeogenesis. Unlike other key metabolic enzymes, PEPCK is a monomeric enzyme with no known physiological regulators of function. Our structural studies demonstrate that in contrast to current understanding, PEPCK contains a hidden allosteric stite. Ligand binding at this site induces a conformational change, precluding nucleotide binding. In order to support our hypothesis and our kinetic data we require high-resolution data on complexes of PEPCK with a series of inhibitors that bind to this site. This data will allow us to develop a model of molecular recognition at this previously unappreciated regulatory site on PEPCK and determine if this regulation has any relevance to metabolic regulation of PEPCK in vivo.