title: Comparison of proposed putative active conformations of myelin basic protein epitope 87-99 linear altered peptide ligands by spectroscopic and modelling studies: the role of positions 91 and 96 in T-cell receptor activation.
abstract: This work proposes a structural motif for the inhibition of experimental autoimmune encephalomyelitis (EAE) by the linear altered peptide ligands (APLs) [Ala91,96] MBP87-99 and [Arg91,Ala96] MBP87-99 of myelin basic protein. Molecular dynamics was applied to reveal distinct populations of EAE antagonist [Ala91,96] MBP87-99 in solution, in agreement with NOE data. The combination of the theoretical and experimental results led to the identification of a putative active conformation. This approach is of value as no crystallographic data is available for the APL-receptor complex. TCR contact residue Phe89 has an altered topology in the putative bioactive conformations of both APLs with respect to the native peptide, as found via crystallography; it is no longer prominent and solvent exposed. It is proposed that the antagonistic activity of the APLs is due to their binding to MHC, preventing the binding of self-myelin epitopes, with the absence of an immunologic response as the loss of some interactions with the TCR hinders activation of T-cells.
authors.affiliation: National Hellenic Research Foundation, Institute of Organic and Pharmaceutical Chemistry, 48 Vassileos Constantinou Avenue, 116 35, Athens, Greece.
authors.forename: Efthimia D
authors.initials: ED
authors.lastname: Mantzourani
authors.forename: Theodore V
authors.initials: TV
authors.lastname: Tselios
authors.forename: Simona Golic
authors.initials: SG
authors.lastname: Grdadolnik
authors.forename: James A
authors.initials: JA
authors.lastname: Platts
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: George N
authors.initials: GN
authors.lastname: Deraos
authors.forename: John M
authors.initials: JM
authors.lastname: Matsoukas
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Mavromoustakos
mesh_terms: D000939:Epitopes; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D004676:Myelin Basic Protein / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry*; D011948:Receptors, Antigen, T-Cell / Q000819:agonists*; D012996:Solutions; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000939:Epitopes; D008024:Ligands; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D012996:Solutions; C516217:myelin basic protein (87-99), Ala(91,96)-; C515876:myelin basic protein (87-99), Arg(91)-Ala(96)-