Residue 259 in protein-tyrosine phosphatase PTP1B and PTPalpha determines the flexibility of glutamine 262

Biochemistry
G H PetersO H Olsen

Abstract

To study the flexibility of the substrate-binding site and in particular of Gln262, we have performed adiabatic conformational search and molecular dynamics simulations on the crystal structure of the catalytic domain of wild-type protein-tyrosine phosphatase (PTP) 1B, a mutant PTP1B(R47V,D48N,M258C,G259Q), and a model of the catalytically active form of PTPalpha. For each molecule two cases were modeled: the Michaelis-Menten complex with the substrate analogue p-nitrophenyl phosphate (p-PNPP) bound to the active site and the cysteine-phosphor complex, each corresponding to the first and second step of the phosphate hydrolysis. Analyses of the trajectories revealed that in the cysteine-phosphor complex of PTP1B, Gln262 oscillates freely between the bound phosphate group and Gly259 frequently forming, as observed in the crystal structure, a hydrogen bond with the backbone oxygen of Gly259. In contrast, the movement of Gln262 is restricted in PTPalpha and the mutant due to interactions with Gln259 reducing the frequency of the oscillation of Gln262 and thereby delaying the positioning of this residue for the second step in the catalysis, as reflected experimentally by a reduction in k(cat). Additionally, in the simulation with th...Continue Reading

References

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Jul 1, 1998·Annual Review of Biophysics and Biomolecular Structure·D BarfordM P Egloff
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Sep 5, 2002·Nature Reviews. Drug Discovery·Theodore O JohnsonMichael R Jirousek

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Citations

Jan 29, 2013·Biochimica Et Biophysica Acta·Paolo PaoliGuido Camici
Feb 8, 2011·Journal of Biomolecular Structure & Dynamics·Elif Ozkirimli Olmez, Burak Alakent
Sep 11, 2007·Biophysical Journal·Lars LinderothGünther H Peters
May 13, 2011·The Journal of Physical Chemistry. B·Jesper J MadsenGünther H Peters
Oct 24, 2006·Nature Reviews. Molecular Cell Biology·Nicholas K Tonks
Dec 30, 2004·The Journal of Biological Chemistry·Arnoud GroenJeroen den Hertog
Apr 11, 2007·Journal of the American Chemical Society·Günther H PetersThomas L Andresen

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