Recent major advances in the elucidation of structurefunction relationships of the gonadotropins, hCG and LH, and their common receptor (LHR) include determination of the crystal structure of hydrogen fluoride (HF)-treated hCG [1, 2], characterization of LHR cDNAs from several species (cf.[3] for review), and determination of the genomic organization of the LHR gene [4, 5]. Coupled with the results of earlier and more recent gonadotropin/receptor investigations, these breakthroughs have placed the field on a firm molecular foundation and have opened up numerous new avenues of study.

The crystal structure of HF-treated hCG revealed many surprises: the holoprotein is quite asymmetrical with loops of the a and subunits intertwined to form a relatively large subunit-subunit contact surface; the a and subunits have similar folding patterns, although there is no significant homology in their amino acid sequences; a cystineknot motif, consisting of three disulfides, is present in each subunit and is similar to that observed in several growth factors; and a portion of the 13 subunit, consisting of amino acid residues 90-110, wraps over the ao subunit forming what has been termed a seat belt (Fig. la). This latter observation is of particular interest when compared with the results on the kinetics and pathway of hCGP folding and its association with a [6]. It was found that several of the disulfides form in hCGj3, followed by association with oa; finally closure of the hCGP 26-110 disulfide locks the seat belt into place and stabilizes the holoprotein. The availability of a three-dimensional structure permitted the results of previous studies on hCG using chemical modifications [7-9], synthetic peptides [10-12], limited proteolysis [13-17], protein engineering to produce hormone chimeras [18], and site-directed mutagenesis [19-26] to be interpreted on a molecular basis. Also, the availability of a structure for the heterodimer has spawned many new investigations, with emphasis on site-directed mutagenesis [27-32] and hormone chimeras [33], aimed at probing hormone-receptor contact sites. These findings have resulted in the identification of many amino acid residues on both