The objective of this research is to define the relative energetics of binding interactions between peptides and MHC class II proteins. Helper T cells are activated by the interaction of an antigen receptor on the T cell with ligands expressed on the surface of other cells. These ligands are complexes of peptides bound to MHC class II proteins. The peptide is bound in a groove on the membrane distal face of the protein. Binding interactions include an array of hydrogen bonds from MHC sidechains to the peptide backbone and pockets in the peptide-binding groove on which peptide sidechains reside. While much is known about the structure of these complexes, the relative contributions of the different binding interactions to the overall stabilities of the complexes are not unknown. We propose to systematically eliminate specific hydrogen-bond and pocket interactions for a variety of peptide-MHC complexes and evaluate their contribution the stabilities. These results will define the rules for peptide binding to MHC class II proteins. The binding rules will greatly aid analyses of antigenic peptide-MHC complexes and the identification of T-cell epitopes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059746-03
Application #
6520065
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Marino, Pamela
Project Start
2000-05-01
Project End
2002-11-30
Budget Start
2002-05-01
Budget End
2002-11-30
Support Year
3
Fiscal Year
2002
Total Cost
$107,369
Indirect Cost
Name
University of Washington
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Bandyopadhyay, Arunima; Arneson, Lynne; Beeson, Craig et al. (2008) The relative energetic contributions of dominant P1 pocket versus hydrogen bonding interactions to peptide:class II stability: implications for the mechanism of DM function. Mol Immunol 45:1248-57
McFarland, Benjamin J; Katz, John F; Sant, Andrea J et al. (2005) Energetics and cooperativity of the hydrogen bonding and anchor interactions that bind peptides to MHC class II protein. J Mol Biol 350:170-83
Reid, Philip J; Loftus, Christine; Beeson, Craig C et al. (2003) Evaluating the potential of fluorinated tyrosines as spectroscopic probes of local protein environments: a UV resonance Raman study. Biochemistry 42:2441-8
McFarland, Benjamin J; Beeson, Craig (2002) Binding interactions between peptides and proteins of the class II major histocompatibility complex. Med Res Rev 22:168-203
McFarland, B J; Katz, J F; Beeson, C et al. (2001) Energetic asymmetry among hydrogen bonds in MHC class II*peptide complexes. Proc Natl Acad Sci U S A 98:9231-6