Structural biology of human follitropin and its receptor.

In this review, the current understanding of structure-activity relationships of human follitropin and of the extracellular domain of its receptor is described. Comprehensive mutagenesis of human follitropin combined with the three-dimensional structure of human follitropin has ushered in a new era of understanding of how this complex hormone binds to and activates its receptor. Comparison of human choriogonadotropin and follitropin structures has proved invaluable in understanding how these human glycoprotein hormones have conserved primary sequence that enables high affinity binding while diverging in amino acids that provide specificity. Moreover, by comparison of the structures of deglycosylated and glycosylated human choriogonadotropin and glycosylated human follitropin, there appears to be no influence of oligosaccharides upon backbone conformation of human glycoprotein hormones. Extensive structure-activity relationships of human follitropin receptor have been studied, and new insights gained here as well. These studies indicate that follitropin binds to the central module of the extracellular domain of the follitropin receptor. Biophysical analyses of purified follitropin receptor extracellular domain further revealed conformational changes affected by hormone binding and by the solvent environment. Further, secondary structure analysis of the purified extracellular domain of follitropin receptor favors the leucine-rich repeat motif model of the glycoprotein hormone receptors. Together, the studies indicate that there are only a few residues that contribute to the overall energy of binding. Formation of a weak collisional complex between follitropin and its receptor likely involves complementation of compatible surfaces and steric hindrance by oligosaccharides, followed by conformational change and formation of active site residue salt bridges. In this regard and in light of these new data, current models of the glycoprotein hormone receptors may need to be re-evaluated.