Regulation of an Enzyme by Phosphorylation at the Active Site

The isocitrate dehydrogenase of Escherichia coli is an example of a ubiquitous class of enzymes that are regulated by covalent modification. In the three-dimensional structure of the enzyme-substrate complex, isocitrate forms a hydrogen bond with Ser$^{113}$, the site of regulatory phosphorylation....

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 1990-08, Vol.249 (4972), p.1012-1016
Main Authors: Hurley, James H., Dean, Antony M., Sohl, Julie L., Koshland, Daniel E., Stroud, Robert M.
Format: Article
Language:English
Subjects:
Active sites
Amino Acid Sequence
Analytical, structural and metabolic biochemistry
Binding Sites
Biochemistry
Biological and medical sciences
Crystallography
Crystals
Electrostatics
Enzyme regulation
Enzymes
Enzymes and enzyme inhibitors
Escherichia coli
Escherichia coli - enzymology
Escherichia coli - genetics
Fundamental and applied biological sciences. Psychology
Homeostasis
Hydrogen bonds
Isocitrate Dehydrogenase - genetics
Isocitrate Dehydrogenase - metabolism
Isocitrates
Models, Molecular
Molecular Sequence Data
Molecules
Oxidoreductases
Phosphorylation
Protein Conformation
Proteins
R factors
Regulation
Research Article
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Summary:The isocitrate dehydrogenase of Escherichia coli is an example of a ubiquitous class of enzymes that are regulated by covalent modification. In the three-dimensional structure of the enzyme-substrate complex, isocitrate forms a hydrogen bond with Ser$^{113}$, the site of regulatory phosphorylation. The structures of Asp$^{113}$ and Glu$^{113}$ mutants, which mimic the inactivation of the enzyme by phosphorylation, show minimal conformational changes from wild type, as in the phosphorylated enzyme. Calculations based on observed structures suggest that the change in electrostatic potential when a negative charge is introduced either by phosphorylation or site-directed mutagenesis is sufficient to inactivate the enzyme. Thus, direct interaction at a ligand binding site is an alternative mechanism to induced conformational changes from an allosteric site in the regulation of protein activity by phosphorylation.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.2204109