Protein tyrosine phosphatases: structure and function, substrate specificity, and inhibitor development

Annu Rev Pharmacol Toxicol. 2002;42:209-34. doi: 10.1146/annurev.pharmtox.42.083001.144616.

Abstract

Protein tyrosine phosphatases (PTPs) are signaling enzymes that control a diverse array of cellular processes. Malfunction of PTP activity is associated with a number of human disorders. Recent genetic and biochemical studies indicate that PTPs represent a novel platform for drug discovery. Detailed knowledge of PTP substrate specificity and the wealth of structural data on PTPs provide a solid foundation for rational PTP inhibitor design. This review summarizes a correlation of PTP structure and function from mutagenesis experiments. The molecular basis for PTP1B and MKP3 substrate recognition is discussed. A powerful strategy is presented for creating specific and high-affinity bidentate PTP inhibitors that simultaneously bind both the active site and a unique adjacent site. Finally, recent advances in the development of potent and selective inhibitors for PTP1B and Cdc25 are described.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Binding Sites
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Protein Tyrosine Phosphatases / antagonists & inhibitors
  • Protein Tyrosine Phosphatases / chemistry*
  • Protein Tyrosine Phosphatases / physiology
  • Substrate Specificity

Substances

  • Enzyme Inhibitors
  • Protein Tyrosine Phosphatases