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A computational analysis of substrate binding strength by phosphorylase kinase and protein kinase A
Author(s) -
Brinkworth Ross I.,
Horne James,
Kobe Bostjan
Publication year - 2002
Publication title -
journal of molecular recognition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.401
H-Index - 79
eISSN - 1099-1352
pISSN - 0952-3499
DOI - 10.1002/jmr.563
Subject(s) - substrate (aquarium) , kinase , enzyme , glycogen phosphorylase , chemistry , biochemistry , sh3 domain , protein kinase a , biophysics , biology , ecology , proto oncogene tyrosine protein kinase src
Protein kinases exhibit various degrees of substrate specificity. The large number of different protein kinases in the eukaryotic proteomes makes it impractical to determine the specificity of each enzyme experimentally. To test if it were possible to discriminate potential substrates from non‐substrates by simple computational techniques, we analysed the binding enthalpies of modelled enzyme–substrate complexes and attempted to correlate it with experimental enzyme kinetics measurements. The crystal structures of phosphorylase kinase and cAMP‐dependent protein kinase were used to generate models of the enzyme with a series of known peptide substrates and non‐substrates, and the approximate enthalpy of binding assessed following energy minimization. We show that the computed enthalpies do not correlate closely with kinetic measurements, but the method can distinguish good substrates from weak substrates and non‐substrates. Copyright © 2002 John Wiley & Sons, Ltd.