PTP catalytic mechanism
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Transcript of PTP catalytic mechanism
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PTP catalytic mechanism
the general acid
the general base
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WPD loop
D to A mutant
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WT (active) PTPs
DA (trapping) PTPs
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BackgroundPTP1B Knock Out Mice
PTP1B -/- mice display enhanced sensitivity to insulin
PTP1B -/- mice are resistant to development of obesity and Type 2 diabetes
(Elchebly et al. Science (1999) 83, 1544-1548) (Klaman et al. Mol Cell Biol (2000) 20, 5479-89)
PTP1B -/-PTP1B +/+
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Inhibition of the Insulin Receptor PTP may Enhance Insulin Signaling
PTP
Prolonged or Enhanced Signal
Transient Signal
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Structure of the PTP1B-IR peptide complex
R1164
pY1163 pY1162
D1161
Arg47
Arg24 Phe182
G1166
Asp48
Arg254
Tyr46
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S.R. Hubbard, (1997) EMBO J., 16, 5573-5581
IRTK Activation segment: DIpY1158ETDpY1162pY1163RKGG
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Kinetic Constants for Dephosphorylation of IR Activation Loop Peptide by PTP1B
RDIpY1158ETDpY1162pY1163RKGGKGLLIR-peptide
Km
[M]
pY-1158 > 100
pY-1162 > 100
pY-1163 > 100
pY-1162,1163
14 ± 1.1
pY-1158,
1162,1163 7.9 ± 1.3
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Insulin
Insulin ReceptorPTK
Signaling Response
PTP1B
PTP1B and insulin signaling
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Suppression of PTP1B expression by RNAi may enhance tyrosine phosphorylation of IR
PTP
Prolonged or Enhanced Signal
Transient Signal
972
1158
11621163