MM-GBSA binding free energy decomposition and T cell receptor engineering.

Details

Serval ID
serval:BIB_B8E3897E24CA
Type
Article: article from journal or magazin.
Publication sub-type
Review (review): journal as complete as possible of one specific subject, written based on exhaustive analyses from published work.
Collection
Publications
Institution
Title
MM-GBSA binding free energy decomposition and T cell receptor engineering.
Journal
Journal of Molecular Recognition
Author(s)
Zoete V., Irving M.B., Michielin O.
ISSN
1099-1352[electronic], 0952-3499[linking]
Publication state
Published
Issued date
2010
Volume
23
Number
2
Pages
142-152
Language
english
Abstract
Recognition by the T-cell receptor (TCR) of immunogenic peptides (p) presented by class I major histocompatibility complexes (MHC) is the key event in the immune response against virus infected cells or tumor cells. The major determinant of T cell activation is the affinity of the TCR for the peptide-MHC complex, though kinetic parameters are also important. A study of the 2C TCR/SIYR/H-2Kb system using a binding free energy decomposition (BFED) based on the MM-GBSA approach had been performed to assess the performance of the approach on this system. The results showed that the TCR-p-MHC BFED including entropic terms provides a detailed and reliable description of the energetics of the interaction (Zoete and Michielin, 2007). Based on these results, we have developed a new approach to design sequence modifications for a TCR recognizing the human leukocyte antigen (HLA)-A2 restricted tumor epitope NY-ESO-1. NY-ESO-1 is a cancer testis antigen expressed not only in melanoma, but also on several other types of cancers. It has been observed at high frequencies in melanoma patients with unusually positive clinical outcome and, therefore, represents an interesting target for adoptive transfer with modified TCR. Sequence modifications of TCR potentially increasing the affinity for this epitope have been proposed and tested in vitro. T cells expressing some of the proposed TCR mutants showed better T cell functionality, with improved killing of peptide-loaded T2 cells and better proliferative capacity compared to the wild type TCR expressing cells. These results open the door of rational TCR design for adoptive transfer cancer therapy.
Keywords
HLA-A2 Antigen/chemistry, HLA-A2 Antigen/immunology, Humans, Major Histocompatibility Complex, Models, Molecular, Peptides/chemistry, Peptides/immunology, Protein Binding/immunology, Protein Structure, Tertiary, Receptors, Antigen, T-Cell/chemistry, Receptors, Antigen, T-Cell/immunology
Pubmed
Web of science
Create date
25/08/2010 13:13
Last modification date
20/08/2019 15:26
Usage data