Structure of human chorionic gonadotropin at 2.6 å resolution from MAD analysis of the selenomethionyl protein

Background Human chorionic gonadotropin (hCG) is a placental hormone that stimulates secretion of the pregnancy-sustaining steroid progesterone. It is a member of a family of glycoprotein hormones that are disulfide-rich heterodimers, with a common α- chain and distinctive β-chains specific to their particular G- protein linked receptors. Results We have produced recombinant hCG in mammalian cells as the selenomethionyl protein, and have determined its structure (after partial deglycosylation) at 2.6 å resolution from multiwavelength anomalous diffraction (MAD) measurements. Despite only limited sequence similarity (10 % identity), the α- and β-subunits of hCG have similar tertiary folds. Each subunit has a cystine-knot motif at its core of extended hairpin loops. There is a very extensive subunit interface featuring two inter-chain β-sheets and a unique, disulfide-tethered ‘arm’ from the β-subunit which ‘embraces’ the α- subunit. The carboxy-terminal peptide of the β-subunit, which is rich in O-linked sugars, is disordered. Conclusions Structural and sequence comparisons indicate an evolutionary homology, albeit remote, between the glycoprotein hormone chains and other cystine-knot proteins, notably platelet-derived growth factor. Segments of the α- and β-chains that have been convincingly implicated in receptor binding by hCG are juxtaposed on one side of the molecule. A glycosylation site implicated in signal transduction but not in binding is also close to the presumed binding site suggesting a possible coupling between ligand binding and signaling. This study with selenomethionyl protein produced in mammalian cells extends the realm of MAD phasing.