How insulin-like growth factor I binds to a hybrid insulin receptor type 1 insulin-like growth factor receptor

Abstract

Monomers of the insulin receptor and type 1 insulin-like growth factor receptor (IGF-1R) can combine stochastically to form heterodimeric hybrid receptors. These hybrid receptors display ligand binding and signalling properties that differ from those of the homodimeric receptors. Here, we describe the cryo-electron microscopy structure of such a hybrid receptor in complex with insulin-like growth factor I. The structure (ca 3.7 Å resolution) displays a single insulin-like growth factor I (IGF-I) ligand, bound in a similar fashion to that seen for IGFs in complex with IGF-1R. The IGF-I ligand engages the first leucine-rich-repeat domain and cysteine-rich region of the IGF-1R monomer (rather than those of the insulin receptor monomer), consistent with the determinants for IGF binding residing in the IGF-1R cysteine-rich region. The structure broadens our understanding of this receptor family and assists in delineating the key structural motifs involved in binding the respective ligands within the family.