Crystal structure of human insulin-like growth factor-1: Detergent bindinginhibits binding protein interactions

Despite efforts spanning considerably more than a decade, a high-resolution view of the family of proteins known as insulin-like growth factors (IGFs) has remained elusive. IGF-I consists of three helical segments which are c onnected by a 12-residue linker known as the C-region. NMR studies of membe rs of this family reveal a dynamic structure with a topology resembling ins ulin but little structural definition in the C-region. We have crystallized IGF-1 in the presence of the detergent deoxy big CHAPS, and determined its structure at 1.8 Angstrom resolution by multiwavelength anomalous diffract ion, exploiting the anomalous scattering of a single bromide ion and six of the seven sulfur atoms of IGF-1. The structure reveals a well-defined conf ormation for much of the C-region, which extends away from the core of IGF- l and has residues known to be involved in receptor binding prominently dis played in a type II beta -turn. In the crystal, these residues form a dimer interface, but analytical ultracentrifugation experiments demonstrate that at physiological concentrations IGF-1 is monomeric. A single detergent mol ecule contacts residues known to be important for IGF-1 binding protein (IG FBP) interactions. Biophysical and biochemical data show that the detergent binds to IGF-1 specifically and blocks binding of IGFBP-1 and IGFBP-3.