Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 275, Issue 39, Pages 30394-30398Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M003524200
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- NCI NIH HHS [CA74305] Funding Source: Medline
- NIDDK NIH HHS [DK52916, DK50074] Funding Source: Medline
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The interaction of a synthetic tetrafluorotyrosyl peptide substrate with the activated tyrosine kinase domain of the insulin receptor was studied by steady-state kinetics and x-ray crystallography. The pH-rate profiles indicate that the neutral phenol, rather than the chemically more reactive phenoxide ion, is required for enzyme-catalyzed phosphorylation. The pK(alpha) of the tetrafluorotyrosyl hydroxyl is elevated 2 pH units on the enzyme compared with solution, whereas the phenoxide anion species behaves as a weak competitive inhibitor of the tyrosine kinase. A structure of the binary enzyme-substrate complex shows the tetrafluorotyrosyl OH group at hydrogen bonding distances from the side chains of Asp(1132) and Arg(1136), consistent with elevation of the pK(alpha). These findings strongly support a reaction mechanism favoring a dissociative transition state.
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