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Allosteric inhibition of PTP1B activity by selective modification of a non-active site cysteine residue.
- Source :
-
Biochemistry [Biochemistry] 2005 May 31; Vol. 44 (21), pp. 7704-12. - Publication Year :
- 2005
-
Abstract
- The fluorogenic reagent 4-(aminosulfonyl)-7-fluoro-2,1,3-benzoxadiazole (ABDF) attenuates the functional activity of the protein tyrosine phosphatase PTP1B by reacting selectively with a single cysteine residue, leaving other cysteines in the protein unmodified. This modification reduces Vmax without substantially affecting substrate binding (Km), indicative of an allosteric mode of inhibition. Consistent with this, the cysteine residue modified by ABDF, Cys 121, lies outside the catalytic site but makes interactions with residues that contact His 214, which has been shown to be important for catalysis. Cys 121 is highly conserved among phosphatases, and ABDF also inhibits TC-PTP and LAR. These findings illustrate that targeting cysteine residues outside catalytic sites may be exploited in allosterically regulating enzymes. Moreover, these results suggest a new strategy for inhibiting a promising diabetes target.
- Subjects :
- Allosteric Regulation
Allosteric Site
Animals
CHO Cells
Catalysis
Cricetinae
Enzyme Inhibitors chemistry
Fluorescence Polarization
Fluorescent Dyes chemistry
Humans
Insulin physiology
Kinetics
Oxadiazoles chemistry
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Protein Tyrosine Phosphatases chemistry
Signal Transduction physiology
Spectrometry, Mass, Electrospray Ionization
Cysteine metabolism
Protein Tyrosine Phosphatases antagonists & inhibitors
Protein Tyrosine Phosphatases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0006-2960
- Volume :
- 44
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 15909985
- Full Text :
- https://doi.org/10.1021/bi047417s