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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/Creator:||Mantzourani, Efthimia D.|
Tselios, Theodore V.
Matsoukas, John M.
Platts, James A.
Mavromoustakos, Thomas M.
Grdadolnik, Simona Golic
|Type:||Journal Article (Scientific Journal article)|
|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 MBP87-99 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 MBP83-96 (human sequence numbering) in the HLA-DR2b complex. The structural motif for the agonist-antagonist activity is discussed.|
|Journal Title:||Bioorganic & Medicinal Chemistry|
|Subject Category:||Science::Biology (General)|
Medicine::Pharmacy and materia medica
|Keywords:||NMR; molecular dynamics; bioactive conformation; agonist-antagonist activity; Chemistry, Medicinal|
|Other Identifiers:||DOI: http://dx.doi.org/10.1016/j.bmc.2007.11.083|
|Journal web Location :||http://www.elsevier.com/locate/bmc|
|Rights holder:||© 2008 Elsevier Ltd. All rights reserved.|