The Y279 residue forms part of the active site (i.e., pTyr binding pocket) and plays a role in positioning a substrate pTyr for hydrolysis.32 Y279 is also in proximity to the catalytic cysteine (C459, 8.2 Å; PDB:3ZM0), and mutations at this tyrosine are inactivating and commonly found in individuals with LEOPARD syndrome.33,34 DML189 also modified the analogous Y279 positions in the SHP1 (Y276) and PTP1B (Y46) catalytic domains. Here, NR0B2 is linked to Noonan syndrome with multiple lentigines.