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PNAS 100 (1): 74-79

Copyright © 2003 by the National Academy of Sciences.

From the Cover

BIOLOGICAL SCIENCES / BIOCHEMISTRY

Structural basis and prediction of substrate specificity in protein serine/threonine kinases

Ross I. Brinkworth, Robert A. Breinl, and Bostjan Kobe*

Department of Biochemistry and Molecular Biology and Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia

Received for publication July 16, 2002.

Abstract: The large number of protein kinases makes it impractical to determine their specificities and substrates experimentally. Using the available crystal structures, molecular modeling, and sequence analyses of kinases and substrates, we developed a set of rules governing the binding of a heptapeptide substrate motif (surrounding the phosphorylation site) to the kinase and implemented these rules in a web-interfaced program for automated prediction of optimal substrate peptides, taking only the amino acid sequence of a protein kinase as input. We show the utility of the method by analyzing yeast cell cycle control and DNA damage checkpoint pathways. Our method is the only available predictive method generally applicable for identifying possible substrate proteins for protein serine/threonine kinases and helps in silico construction of signaling pathways. The accuracy of prediction is comparable to the accuracy of data from systematic large-scale experimental approaches.

* To whom correspondence should be addressed. E-mail: b.kobe{at}mailbox.uq.edu.au.

Edited by Susan S. Taylor, University of California at San Diego, La Jolla, CA, and approved November 18, 2002

This paper was submitted directly (Track II) to the PNAS office.

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