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.

Mantzourani ED,  Platts JA, Brancale A, Mavromoustakos TM, Tselios TV.

Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue , 116 35 Athens , Greece ; Department of Chemistry, University of Patras, 265 00 Rion, Patras , Greece .

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 [Arg(91), Ala(96)] MBP (87-99) and [Ala(91,96)] MBP (87-99). 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 His(88) and Phe(89) 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 [Arg(91), Ala (96)] MBP (87-99) and [ Ala (91,96)] MBP (87-99): His(88) and Phe(89) 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.

PMID : 17392002 [PubMed - as supplied by publisher]

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