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2-(Oxalyl-amino)-4,7-dihydro-5if-

thieno[2,3-c]thiopyran-3-carboxylic acid

Apo structure (C215S mutant)

Peters et al. 2000

Scapin et al. 2001

1PTY Phosphotyrosine (C215S mutant)

40 1PXH N-{l-[5-(l -Carbamoyl-2-mercapto-ethylcarbamoyl) -

pentylcarbamoyl]-2-[4-(difluoro-phosphono-methyl)-phenyl]-ethyl}-3-{2-[4-(difluoro-phosphono-methyl)-phenyl] -acetylamino}-succinamic acid 1Q1M 5-{2-Fluoro-5-[3-(3-hydroxy-2-methoxy-carbonyl-phenoxy) -propenyl] -phenyl}-isoxazole-3-carboxylic acid

Puius et al. 1997

Sun et al. 2003

Liu et al. 2003b

Fig. 2 Schematic representation of the catalytic mechanism of PTPs.1-3: Cys215 in the P-loop (PTP1B numbering used throughout) acts as a nucleophile, which attacks the phosphate leading to the formation of a cysteine-phosphate intermediate. In this first step of catalysis, Asp181 in the WPD loop acts as a general acid donating a proton to the leaving group. 4-6: In the second step of catalysis, the thiol-phosphate intermediate is attacked by a water molecule that is positioned optimally by Gln262

Fig. 2 Schematic representation of the catalytic mechanism of PTPs.1-3: Cys215 in the P-loop (PTP1B numbering used throughout) acts as a nucleophile, which attacks the phosphate leading to the formation of a cysteine-phosphate intermediate. In this first step of catalysis, Asp181 in the WPD loop acts as a general acid donating a proton to the leaving group. 4-6: In the second step of catalysis, the thiol-phosphate intermediate is attacked by a water molecule that is positioned optimally by Gln262

by Gln262 (Pannifer et al. 1998), hence leading to the release of phosphate (Fig. 2, parts 4-6). The understanding of the catalytic machinery in PTPs has been greatly facilitated by several seminal mutational and X-ray studies (Barford et al. 1994; Stuckey et al. 1994; Jia et al. 1995; Schubert et al. 1995; Fauman et al. 1996; Pannifer et al. 1998; Sarmiento et al. 1998).

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