Bifunctional hCG analogs adopt different conformations in LH and FSH receptor complexes

Human reproduction requires specific interactions between follitropin (hFSH ) and its receptor (FSHR) and between lutropin (hLH) or choriogonadotropin (hCG) and the lutropin receptor (LHR). Substitution of hFSH residues betwee n hCG beta -subunit cysteines 11-12 creates a bifunctional analog that bind s both receptors. To understand the basis of this observation, we used anti body probes to compare the conformations of bifunctional analogs before and after they were complexed with each receptor. Introduction of hFSH residue s between cysteines 11-12 changed a distant conformation-sensitive region c reated by the juxtaposition of the subunit aminotermini. This region, found not to contact either receptor, was altered further when bifunctional liga nds bound FSHR. All other surfaces, detected in LWR complexes, were also re cognized in FSHR complexes, an indication that bifunctional ligands bind bo th receptors in similar orientations. These observations suggest that unlik e hCG or hFSH, bifunctional gonadotropins can acquire 'lutropin' and 'folli tropin' conformations, a phenomenon accentuated by receptor contacts. (C) 2 000 Elsevier Science Ireland Ltd. All rights reserved.