Three-dimensional models of gonado-thyrotropin hormone receptor transmembrane domain

The gonado-thyrotropin hormones, including choriogonadotropin, CG, lutropin, LH, follitropin, FSH, and thyrotropin, TSH, bind to membrane receptors belonging to the G protein-coupled receptors family. Graphics computer generated three-dimensional models of the transmembrane domains of these receptors were built and analyzed. Using bacteriorhodopsin as a template, these models were defined using an extensive primary sequence comparison, secondary structure predictions, and three-dimensional homology building. Although the overall topology of the transmembrane domains of the gonado-thyrotropin receptors appeared to be similar to that of the other members of the family, major differences lie in the large size of the pocket defined by the seven helices and its hydrophilic nature. Focusing on the FSH receptor allowed us to analyze the putative hormone binding site in the transmembrane domain. The residues likely to be responsible for the receptor affinity and activation were identified and, surprisingly, disclosed an Asp-His-Thr motif similar to that present in the cleavage site of serine proteases. Together our results substantiate hypotheses claiming that part of the hormone might interact with this region of the receptor. This model represents important working hypotheses to direct future experimental exploration of the gonadotropin receptor binding and activation. Furthermore, it can help in the design of peptidic gonadotropin analogs and nonpeptide mimetics of these hormones critical in the fertility processes.