SHP-1 plays a critical role in human immune systems, especially in regulating B-cell and Tcell signal transduction pathways. Mutations and impaired SHP-1 activities have been linked to the murine motheaten disease and Familial hemophagocytic lymphohistiocytosis, featuring SHP-1 as an intriguing research target for clinical studies. The phosphatase activity of the full- length SHP-1 is autoinhibited at rest by the insertion of an SH2 domain to its active site, while the enzyme resumes the catalytically active conformation upon cellular stimulation. Similar to two of the most characterized PTPs, YopH and PTP1B, SHP-1 contains a mobile WPD-loop, and a static P-loop. The overall secondary structure of SHP-1 is highly superimposable to that of PTP1B according to X-ray studies, especially the signature active site motifs, the WPD-loop and the Ploop.