Conclusions

The information potential about hormone action that can be obtained from the combined use of functional and structural studies is enormous. Significant progress has been made toward understanding the binding events and signal transduction mechanism of hGH through its cell-surface receptor. It has been shown that hGH can dimerize its receptor and that this process is a sequential one. hGH first binds a single receptor molecule in a 1:1 complex, which in turn creates a binding site for the association of a second receptor. The second receptor makes molecular contacts with both hGH and the first bound receptor. For the 1:1 complex, the observation that the energetics of binding are governed by only a few centralized contact residues suggests that the design of small molecule agonists or antagonists may be possible. Such molecules could essentially mimic binding at a large protein-protein interface, but in the context of a compact small molecule.

Obviously, a key step in understanding hormonal molecular recognition is obtaining a three-dimensional structure of hormone-receptor complexes. Such information is crucial for guiding mutagenesis studies and, furthermore, for construction of second generation molecules through the use of phage display (44).

The gap in our understanding between extracellular events and cell activation, growth, and differentiation will undoubtedly be shortened in the years to come. Even though great progress has been made toward identifying the cytosolic ligands for the activated hGHR, information regarding the specific molecular complexes formed after receptor dimeriza-tion is lacking. The precise manner whereby ligand-induced dimerization on the outside of the cell stabilizes the interaction between receptor intracellular domains and cytosolic kinases remains to be understood. In all, understanding the molecular detail of such signaling pathways, from extracellular to intracellular events, is of critical importance for deciphering how cells communicate, proliferate, and differentiate. Molecular-level understanding of these events can potentially allow for the design of clinically relevant agonists and antagonists.

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