Regulation of an enzyme by phosphorylation at the active site

James H. Hurley, Antony M. Dean, Julie L. Sohl, Daniel E. Koshland, Robert M. Stroud

Research output: Contribution to journalArticlepeer-review

209 Scopus citations

Abstract

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 Ser113, the site of regulatory phosphorylation. The structures of Asp113 and Glu113 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.

Original languageEnglish (US)
Pages (from-to)1012-1016
Number of pages5
JournalScience
Volume249
Issue number4972
DOIs
StatePublished - 1990

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