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

Yong Seok Heo, Jung Min Ryu, Sang Myun Park, Jeon Han Park, Hyun Chul Lee, Kwang Yeon Hwang, Jongsun Kim

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 Ki values of 0.06-1.2 μM 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 Å resolution, reveals that MoO3, 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 (MoO3, MoO2, and MoO2Cl2) inhibited PTP-1B with IC50 in the range 5-15 μM.

Original languageEnglish
Pages (from-to)211-223
Number of pages13
JournalExperimental and Molecular Medicine
Volume34
Issue number3
Publication statusPublished - 2002 Jul 31
Externally publishedYes

Fingerprint

Protein Tyrosine Phosphatases
Non-Receptor Type 1 Protein Tyrosine Phosphatase
Edetic Acid
Vanadium Compounds
Cell signaling
Ligands
Atoms
Phosphotyrosine
Molecules
Cytoplasmic and Nuclear Receptors
Phosphoric Monoester Hydrolases
Protein-Tyrosine Kinases
Oxides
Inhibitory Concentration 50
Cysteine
Alkaline Phosphatase
phosphomolybdic acid
Hydrolysis
Catalytic Domain
Crystal structure

Keywords

  • Crystallography
  • Enzyme inhibitors
  • Molybdenum
  • Protein-tyrosine-phosphatase
  • Tungsten compounds

ASJC Scopus subject areas

  • Biochemistry
  • Genetics

Cite this

Structural basis for inhibition of protein tyrosine phosphatases by Keggin compounds phosphomolybdate and phosphotungstate. / Heo, Yong Seok; Ryu, Jung Min; Park, Sang Myun; Park, Jeon Han; Lee, Hyun Chul; Hwang, Kwang Yeon; Kim, Jongsun.

In: Experimental and Molecular Medicine, Vol. 34, No. 3, 31.07.2002, p. 211-223.

Research output: Contribution to journalArticle

Heo, Yong Seok ; Ryu, Jung Min ; Park, Sang Myun ; Park, Jeon Han ; Lee, Hyun Chul ; Hwang, Kwang Yeon ; Kim, Jongsun. / Structural basis for inhibition of protein tyrosine phosphatases by Keggin compounds phosphomolybdate and phosphotungstate. In: Experimental and Molecular Medicine. 2002 ; Vol. 34, No. 3. pp. 211-223.
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