Exploring the structural elements of MHC-peptide-TCR interaction with analogs of VSV-8, an antigenic peptide derived from vesicular stomatitis virus / Naoyuki Gregory Saito.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Saito, Naoyuki Gregory.

Contributor:

Paterson, Yvonne, 1941- advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Biochemistry.

Biochemistry--Penn dissertations.

Penn dissertations--Molecular biophysics.

Molecular biophysics--Penn dissertations.

Biochemistry and Molecular biophysics.

Biochemistry and Molecular Biophysics.

Academic Dissertations as Topic.

Medical Subjects:

Biochemistry and Molecular Biophysics.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Biochemistry.

Biochemistry--Penn dissertations.

Penn dissertations--Molecular biophysics.

Molecular biophysics--Penn dissertations.

Biochemistry and Molecular biophysics.

Physical Description:

xv, 194 pages : color illustrations ; 29 cm

Production:

1998.

Summary:

Antigenic peptides are thought to bind to major histocompatibility complex (MHC) class I molecules through three modes of interaction: van der Waals interaction and to a lesser extent, hydrogen bonding of anchor side chain atoms to residues comprising the binding pockets of the MHC molecule; hydrogen bonding of N- and C-termini to residues at the ends of the binding groove; and hydrogen bonding of peptide backbone atoms to residues lining the binding groove. T cell receptors (TCRs) on surfaces of CD8+ cytotoxic T lymphocytes (CTLs) recognize a molecular surface created from the combination of the antigenic peptide with the MHC class I molecule.

In this work, we explored the structural parameters of this interaction with VSV-8, an H-2Kb restricted antigenic peptide derived from vesicular stomatitis virus, as a model peptide. Retro-inverso (RI) analogs of the VSV-8 peptides were synthesized to determine the contribution of peptide backbone atoms to the stability of the MHC- peptide complex. We found that the peptide backbone atoms greatly contribute to the affinity of the VSV-8 peptide to the H-2Kb molecule. Analysis of the first-order computer models of the RI VSV-8 analogs in complex with the H-2Kb molecule suggested that the stability of the MHC-peptide complex is derived from an extensive network of hydrogen bonds formed between the peptide backbone atoms and the MHC side chain atoms.

Furthermore, P3 and/or P5 side chain analogs of the VSV-8 peptide were also made to explore the role of buried peptide side chains in the conformation of the MHC class I molecular surface recognized by the TCR. We found that fine atomic substitutions of the hydroxyl group with hydrogen, fluorine, or bromine on the buried tyrosine residues resulted in a conformational change in the MHC-peptide complex that can be detected by monoclonal antibodies (mAbs), CTLs, and TCR transfected hybridomas. These results are consistent with a model of the conformation of the MHC class I molecular surface that is exquisitely dependent on the structure of the buried "anchor" residues within the antigenic peptide.

Notes:

Supervisor: Yvonne Paterson.

Thesis (Ph.D. in Biochemistry and Molecular biophysics) -- University of Pennsylvania, 1998.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 99-13515.

OCLC:

187478147