STRUCTURAL PREDICTIONS FOR THE LIGAND-BINDING REGION OF GLYCOPROTEIN HORMONE RECEPTORS AND THE NATURE OF HORMONE-RECEPTOR INTERACTIONS

Background: Glycoprotein hormones influence the development and functi on of the ovary, testis and thyroid by binding to specific high-affini ty receptors. The extracellular domains of these receptors are members of the leucine-rich repeat (LRR) protein superfamily and are responsi ble for the high-affinity binding. The crystal structure of a glycopro tein hormone, namely human choriogonadotropin (hCG), is known, but nei ther the receptor structure, mode of hormone binding, nor mechanism fo r activation, have been established. Results: Despite very low sequenc e similarity between exon-demarcated LRRs in the receptors and the LRR s of porcine ribonuclease inhibitor (RI), the secondary structures for the two repeat sets are found to be alike. Constraints on curvature a nd beta-barrel geometry from the sequence pattern for repeated beta al pha units suggest that the receptors contain three-dimensional structu res similar to that of RI. With the RI crystal structure as a template , models were constructed for exons 2-8 of the receptors. The model fo r this portion of the choriogonadotropin receptor is complementary in shape and electrostatic characteristics to the surface of hCG at an id entified focus of hormone-receptor interaction. Conclusions: The predi cted models for the structures and mode of hormone binding of the glyc oprotein hormone receptors are to a large extent consistent with curre ntly available biochemical and mutational data. Repeated sequences in beta-barrel proteins are shown to have general implications for constr aints on structure. Averaging techniques used here to recognize the st ructural motif in these receptors should also apply to other proteins with repeated sequences.