Exp Mol Med.  2002 Jul;34(3):211-223.

Structural basis for inhibition of protein tyrosine phosphatases by Keggin compounds phosphomolybdate and phosphotungstate.

• Heo YS
• Ryu JM
• Park SM
• Park JH
• Lee HC
• Hwang KY
• Kim JS

Abstract

Protein-tyrosine phosphatases (PTPs) constitute a family of receptor-like, and cytoplasmic enzymes, which catalyze the dephosphorylation of phosphotyrosine residues in a variety of receptors and signaling molecules. Together with protein tyrosine kinases (PTKs), PTPs are critically involved in regulating many cellular signaling processes. In this study, diverse compounds were screened for PTP inhibition and selectively screened for inhibitors with the end product inhibition properties. Among phosphate analogues and their derivatives for PTP inhibition, Keggin compounds phosphomolybdate (PM) and phosphotungstate (PT) strongly inhibited both PTP-1B and SHP-1, with K(i) values of 0.06-1.2 micromM in the presence of EDTA. Unlike the vanadium compounds, inhibition potencies of PM and PT were not significantly affected by EDTA. PM and PT were potent, competitive inhibitors for PTPs, but relatively poor inhibitors of Ser/Thr phosphatase. Interestingly, PM and PT did not inhibit alkaline phosphatase at all. The crystal structure of PTP-1B in complex with PM, at 2.0 A resolution, reveals that MoO(3), derived from PM by hydrolysis, binds at the active site. The molybdenium atom of the inhibitor is coordinated with six ligands: three oxo-ligands, two apical water molecules and a S atom of the catalytic cysteine residue. In support of the crystallographic finding, we observed that molybdenium oxides (MoO(3), MoO(2), and MoO(2)Cl(2)) inhibited PTP-1B with IC(50) in the range 5-15 micromM.

Keyword

Protein-tyrosine-phosphatase; molybdenum; tungsten compounds; enzyme inhibitors; crystallography

MeSH Terms

Binding, Competitive
Catalytic Domain
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Edetic Acid/pharmacology
Enzyme Inhibitors/*pharmacology
Human
Inhibitory Concentration 50
Kinetics
Models, Molecular
Molybdenum/*pharmacology
Phosphoric Acids/*pharmacology
Protein Structure, Tertiary
Protein-Tyrosine-Phosphatase/*antagonists & inhibitors/*chemistry/isolation & purification
Substrate Specificity
Tungsten Compounds/*pharmacology