One of the central questions in immunology is how a limited set of MHC class I molecules expressed in each individual can interact with a large number of different peptide antigens. Our objective of this proposal is to provide the structural basis of this broad but selective recognition of peptides with class I molecules by immunological, biochemical and biophysical approaches. The and in chemotherapy and drug design. The specific goal is to specify the detail interactions of murine MHC class I molecules with peptides and to determine their three-dimensional structures by x-ray crystallography. Significant immunological work has focussed on the mouse MHC system and this first detailed x-ray study of a mouse I, H-2Kb will be invaluable for analysis of the vast body of immunological data on antigen presentation and T-cell recognition (TCR).
The specific aims of our proposal are as follows: 1. Three-dimensional Structures of Kb-Peptide (8-9 mer) Complexes 2. Three-dimensional Structures of Kb with Longer Peptides 3. Three-dimensional Structures of Empty Kb Molecules 4. Biochemical and Crystallographic Analysis of Mutant Kb 5. Biochemical and Crystallographic Analysis of CD1, A Non-classical MHC Class I Molecule 6. Biochemical Analysis and Crystallization of Other Murine MHC Class I 7. Design and Characterization of MHC Class I Agonists and Antagonists A combined immunological, biochemical and biophysical approach will be used to understand the specific binding of viral, microbial and self peptides. The structures of the empty or unliganded Kb will show whether conformational changes in the MHC accompany peptide binding as has been, seen for example, in the binding of peptides for Fabs. The function of class I molecules will be probed by the analysis of murine class I mutants (H-2Kbm) as well as the study of a non-classical class I antigen, CD1. A further goal is to understand ad compare how other murine MHC1 molecules such as H-2Ld recognize and interact with peptides. The long term goal is to understand the biologically important signal transduction complexes of MHC, TCR and accessory molecules such as CD-8. This proposal represents a joint effort by two laboratories to elucidate the structure and function of murine MHC class I molecules.
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