| Abstract | This work reports molecular dynamics studies at the receptor level of the immunodominant myelin basic protein (MBP) epitope 87-99 implicated in multiple sclerosis, and its antagonists altered peptide ligands (APLs), namely [Arg91, Ala96] MBP87-99 and [Ala91,96] MBP87-99. The interaction of each peptide ligand with the receptor human leukocyte antigen HLA-DR2b was studied, starting from X-ray structure with pdb code: 1ymm. This is the first such study of APL-HLA-DR2b complexes, and hence the first attempt to gain a better understanding of the molecular recognition mechanisms that underlie TCR antagonism by these APLs. The amino acids His88 and Phe89 serve as T-cell receptor (TCR) anchors in the formation of the trimolecular complex TCR-peptide-HLA-DR2b, where the TCR binds in a diagonal, off-centered mode to the peptide-HLA complex. The present findings indicate that these two amino acids have a different orientation in the APLs [Arg91, Ala96] MBP87-99 and [Ala91,96] MBP87-99: His88 and Phe89 remain buried in HLA grooves and are not available for interaction with the TCR. We propose that this different topology could provide a possible mechanism of action for TCR antagonism. |
| Authors | Efthimia D Mantzourani, James A Platts, Andrea Brancale, Thomas M Mavromoustakos, Theodore V Tselios
(Affiliation: Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 116 35 Athens, Greece.)
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| Journal | Journal of molecular graphics & modelling
(J Mol Graph Model)
Vol. 26
Issue 2
Pg. 471-81
(Sep 2007)
ISSN: 1093-3263 United States |
| PMID | 17392002
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- HLA-DR2 Antigen
- Immunodominant Epitopes
- Myelin Basic Proteins
- Peptide Fragments
- Receptors, Antigen, T-Cell
- myelin basic protein 87-99
|
| Topics |
- Computer Simulation
- HLA-DR2 Antigen
(chemistry, metabolism)
- Immunodominant Epitopes
(chemistry, metabolism)
- Models, Molecular
- Molecular Structure
- Multiple Sclerosis
(metabolism)
- Myelin Basic Proteins
(chemistry, metabolism)
- Peptide Fragments
(chemistry, metabolism)
- Protein Conformation
- Receptors, Antigen, T-Cell
(chemistry, metabolism)
- Structure-Activity Relationship
- Thermodynamics
|
