Molecular mechanism of inhibition by new cytokine inhibitors. (Left) PIAS inhibits DNA-binding activity of STATs through association with activated them. (Center) SOCS-1 inhibits catalytic activity of JAKs by direct interaction with them. (Right) SOCS-3 inhibits catalytic activity of JAKs by binding to receptor complex. JAK, Janus family tyrosine kinases; P, phosphorylation; PIAS, protein inhibitors of activated STATs; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription; Y, tyrosine residue.