Protein tyrosine phosphatases: structure and function, substrate specificity, and inhibitor development.
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.
Zhang
Zhong-Yin
ZY
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA. zyzhang@aecom.yu.edu
D000818:Animals; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000502:physiology; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D017027:Protein Tyrosine Phosphatases