A combined NMR and molecular dynamics simulation study to determine the conformational properties of agonists and antagonists against experimental autoimmune encephalomyelitis

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...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2008-03, Vol.16 (5), p.2171-2182
Main Authors: Mantzourani, Efthimia D., Blokar, Klemen, Tselios, Theodore V., Matsoukas, John M., Platts, James A., Mavromoustakos, Thomas M., Grdadolnik, Simona Golič
Format: Article
Language:English
Subjects:
Agonist–antagonist activity
Alkaline Phosphatase - antagonists & inhibitors
Alkaline Phosphatase - metabolism
Amides - chemistry
Amino Acid Sequence
Animals
Bioactive conformation
Biological and medical sciences
Computer Simulation
Encephalomyelitis, Autoimmune, Experimental - drug therapy
Encephalomyelitis, Autoimmune, Experimental - enzymology
Hydrogen Bonding
Immunomodulators
Magnetic Resonance Spectroscopy
Medical sciences
Models, Molecular
Molecular Conformation
Molecular dynamics
Molecular Sequence Data
Myelin Basic Protein - agonists
Myelin Basic Protein - antagonists & inhibitors
Myelin Basic Protein - chemistry
Myelin Basic Protein - metabolism
NMR
Pharmacology. Drug treatments
Protons
Temperature
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 α 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2007.11.083