CRYSTAL-STRUCTURE OF THE CATALYTIC DOMAIN OF PROTEIN-TYROSINE-PHOSPHATASE SHP-1

The crystal structures of the protein-tyrosine phosphatase SHP-1 catal ytic domain and the complex it forms with the substrate analogue tungs tate have been determined and refined to crystallographic R values of 0.209 at 2.5 Angstrom resolution and 0.207 at 2.8 Angstrom resolution, respectively. Despite low sequence similarity, the catalytic domain o f SKP-1 shows high similarity in secondary and tertiary structures wit h other protein-tyrosine phosphatases (PTPs). In contrast-to the confo rmational changes observed in the crystal structures of PTP1B and Yers inia PTP, the WPD loop (Trp(419)-Pro(428)) in the catalytic domain of SHP-1 moves away from the substrate binding pocket after binding the t ungstate ion. Sequence alignment and structural analysis suggest that the residues in the WPD loop, especially the amino acid following Asp( 421), are critical for the movement of WPD loop on binding substrates and the specific activity of protein-tyrosine phosphatases. Our mutage nesis and kinetic measurements have supported this hypothesis.