THREE DIMENSIONAL STRUCTURAL ANALYSIS OF THE GONADOTROPINS

The primary focus of Project II is the analysis of the three-dimensional structure of the gonadotropins. This project collaborates with Project I and III, which supply some of the reagents and techniques to carry out this program. Solutions of the structures of the active and inactive forms of gonadotropins and their receptor interfaces will enable design of hormone agonists and antagonists which will be useful in the control of fertility. It is not possible to design such reagents without solved structures to supply the precise geometry information about the surfaces of the protein. The specific goals of this project are: (1) to determine the structures of the glycosylated biologically active form of hCG and of neuraminidase- treated hCG and to compare the resulting models to our solved structure of HF-treated hCG, an antagonist of hCG; (2) to determine the structure of the hormone receptor interface of hCG and the LH/CG receptor; (3) to determine the structure of FSH; (4) to determine the structure of the subunits of hCG; (5) to design mutants of hCG from its solved structure to produce an hCG antagonist by decreasing the flexibility of hCG; and (6) to continue to develop important novel technology for NMR solutions of three dimensional structures. The project encompasses biophysical methodology (Crystallography & NMR) to achieve these goals.