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Several examples illustrating the docking of protein-protein complexes are now known. Systems typically include enzyme dockings such as Bovine Pancreatic Trypsin Inhibitor (BPTI) and Trypsin. Based on this success, we are investigating the use of the UCSF DOCK program for larger protein-protein complexes. Specifically, we are using human growth hormone (hGH) to its extracellular domain of its receptor (hGHbp) as our model system (see image above or download this high resolution tiff image [0.6MB]). The 2.8 angstrom crystal structure of the complex consists of one molecule of the four helix bundle growth hormone (hGH) per two molecules of the receptor (hGHbp), the later of which consists of two binding domains. Each molecule of the receptor interacts with hGH using the same amino acids although the two binding sites have no structural similarity.
We are investigating the ability of our current docking and scoring methods to ascertain whether our methods can determine the subtle differences and preferential binding of each of these binding sites of hGHbp to hGH. The set of experiments to be performed for evaluating our methods are: replicating the crystal complex, the independent docking of hGH to site 1 of hGHbp in the absence of site 2, the independent docking of hGH to site 2 of hGHbp in the absence of site 1, the docking of hGH to the hGHbp dimer, and the docking of hGH to mutated hGHbp dimers.
Results from these experiments will be used to refine and enhance these docking and scoring methods to better handle the docking of large protein-protein complexes such as hGH, prolactin, etc.
Acknowledgments: This research is supported by the National Institutes of Health, grants GM08388 (A.C. Hunt, P.I.) and GM31497 (I.D. Kuntz, P.I.), and the National Center for Research Resources, grant P41-RR01081 (T.E. Ferrin, P.I.).
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