title: Molecular dynamics at the receptor level of immunodominant myelin basic protein epitope 87-99 implicated in multiple sclerosis and its antagonists altered peptide ligands: triggering of immune response.
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: Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 116 35 Athens, Greece.
authors: Efthimia D
authors: ED
authors: Mantzourani
authors: James A
authors: JA
authors: Platts
authors: Andrea
authors: A
authors: Brancale
authors: Thomas M
authors: TM
authors: Mavromoustakos
authors: Theodore V
authors: TV
authors: Tselios
mesh_terms: D003198:Computer Simulation; D015802:HLA-DR2 Antigen / Q000737:chemistry / Q000378:metabolism; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009103:Multiple Sclerosis / Q000378:metabolism*; D004676:Myelin Basic Protein / Q000737:chemistry* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D015802:HLA-DR2 Antigen; D016056:Immunodominant Epitopes; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; C115314:myelin basic protein 87-99