Protein tyrosine kinases: Structure, substrate specificity, and drug discovery

F. A. Al-Obeidi, J. J. Wu, Kit Lam

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

Protein tyrosine kinases (PTKs) play a crucial role in many cell regulatory processes. It is therefore not surprising to see that functional perturbation of PTKs results in many diseases. Despite the diverse primary structure organization of various PTKs, the catalytic or kinase domains of various PTKs as well as that of Ser/Thr kinases are generally conserved. The high resolution crystal structure of a few PTKs has been solved in the last few years. In contrast to the well-defined linear peptide substrate motifs recognized by specific Ser/Thr kinases, the identification of specific substrate motifs for PTK has been slow. It is not until recently that through the use of combinatorial peptide library methods that specific recognition motifs for specific PTKs have begun to emerge. Efficient and specific peptide substrates for some PTKs with K(m) at the mid μM range have been identified. Based on these peptide substrates, relatively potent (IC50 at the low μM range) and highly selective pseudosubstrate-based peptide inhibitors have been developed. There has been enormous effort in the development of PTK inhibitors for diseases such as cancer, psoriasis, and osteoporosis. Several new high-throughout PTK assay technologies have recently been described. Small molecules against specific PTK have been developed. Most of them are competitive inhibitors at the ATP binding site. Some of these inhibitors have already been in clinical trial.

Original languageEnglish (US)
Pages (from-to)197-223
Number of pages27
JournalBiopolymers - Peptide Science Section
Volume47
Issue number3
DOIs
StatePublished - 1998
Externally publishedYes

Keywords

  • Cell regulation
  • Drug discovery
  • Protein kinase assays
  • Protein kinase inhibitors
  • Protein tyrosine kinases (PTK)
  • PTK structure
  • Substrate motifs
  • Substrate specificity

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Biophysics

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