Insulin receptor substrate (IRS) is an important ligand in the insulin response of human cells. Insulin receptor substrate (IRS) is an important ligand in the insulin response of human cells. IRS-1, for example, is an IRS protein that contains a phosphotyrosine binding-domain (PTB-domain). In addition, the insulin receptor contains a NPXY motif. The PTB-domain binds the NPXY sequence. Thus, the insulin receptor binds IRS.