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  • Title: A combined NMR and molecular dynamics simulation study to determine the conformational properties of agonists and antagonists against experimental autoimmune encephalomyelitis.
    Author: Mantzourani ED, Blokar K, Tselios TV, Matsoukas JM, Platts JA, Mavromoustakos TM, Grdadolnik SG.
    Journal: Bioorg Med Chem; 2008 Mar 01; 16(5):2171-82. PubMed ID: 18207413.
    Abstract:
    Myelin basic protein (MBP) is one of the best characterized autoantigens causing multiple sclerosis (MS), via a procedure that involves a stable formation of the trimolecular complex of a T-cell Receptor (TCR), an MBP epitope, and the receptor HLA-DR2b. Experimental autoimmune encephalomyelitis (EAE) is considered as an instructive model for MS in humans, and plenty of X-ray data is available for a number of EAE inducing peptide-receptor complexes. To date, though, there are no data available for complexes involving peptides reversing EAE, namely antagonists. Conformational properties of the EAE inducing epitope MBP(87-99) were analyzed in DMSO using the NOE connectivities and vicinal H(N)-H(alpha) coupling constants, and compared with the antagonist altered peptide ligands. A robust method, which is based on a combination of molecular dynamics and energy minimization, is proposed for identifying the putative bioactive conformations. Generated conformations are compared with the known X-ray structure of MBP(83-96) (human sequence numbering) in the HLA-DR2b complex. The structural motif for the agonist-antagonist activity is discussed.
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