Structure and Dynamics of MUC1 Immune Recognition: Significance for Breast Cancer Vaccine Design
EMSL Project ID
3319
Abstract
Generation of a cytotoxic T lymphocyte (CTL) immune response requires an antigenic peptide to be presented to the T cell receptor by Class I MHC molecules. Low affinity MHC Class I-associated peptides derived from self proteins overexpressed in a wide variety of human malignancies provide potential targets for a broad-spectrum, CTL-based immunotherapy of cancer. The immunogenicity of these peptides can be improved by increasing their affinity for Class I MHC molecules. We propose a structural analysis of low-affinity tumor-associated antigenic peptides using NMR spectroscopy to determine the structural and dynamical basis for the observed low-affinity binding to Class I MHC. Upon identifying this basis, we will employ molecular modeling to suggest alterations in peptide sequence that could lead to an effective immunotherapy for the associated cancers. Towards this end, we have generated stable recombinant Class I MHC molecules in complex with selectively 15N/13C-labeled antigenic peptide. Attached spectra show a folded protein with tertiary structure, as well as the need for deuteration of the MHC protein. Subsequently, we have generated deuterated MHC protein with a high yield, and are presently purifying this deuterated MHC in complex with 15N/13C-labeled antigenic peptide. In order to assign the resonances of the labeled complex, we require the use of the NMR spectrometers at EMSL. We do not have a spectrometer available to us with deuterium decoupling capability. Furthermore, the sensitivity increase expected at the higher magnetic field strength of 600 or 750 MHz will allow more timely acquisition of data sets.
Project Details
Project type
Capability Research
Start Date
2003-04-23
End Date
2004-04-26
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
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