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

Authors
 Yong-Seok Heo  ;  Jung Min Ryu  ;  Sang Myun Park  ;  Jeon Han Park  ;  Hyun-Chul Lee  ;  Kwang Yeon Hwang  ;  Jong Sun Kim 
Citation
 EXPERIMENTAL AND MOLECULAR MEDICINE, Vol.34(3) : 211-223, 2002 
Journal Title
EXPERIMENTAL AND MOLECULAR MEDICINE
ISSN
 1226-3613 
Issue Date
2002
MeSH
Binding, Competitive ; Catalytic Domain ; Crystallography, X-Ray ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Edetic Acid/pharmacology ; Enzyme Inhibitors/pharmacology* ; Humans ; Inhibitory Concentration 50 ; Kinetics ; Models, Molecular ; Molybdenum/pharmacology* ; Phosphoric Acids/pharmacology* ; Protein Structure, Tertiary ; Protein Tyrosine Phosphatases/antagonists & inhibitors* ; Protein Tyrosine Phosphatases/chemistry* ; Protein Tyrosine Phosphatases/isolation & purification ; Substrate Specificity ; Tungsten Compounds/pharmacology*
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 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 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 µM.
Files in This Item:
T200210414.pdf Download
DOI
10.1038/emm.2002.30
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jong Sun(김종선) ORCID logo https://orcid.org/0000-0002-3149-669X
Park, Jeon Han(박전한) ORCID logo https://orcid.org/0000-0001-9604-3205
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/144517
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