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

Mantzourani, Efthymia D., Tselios, Theodore V., Grdadolnik, Simona Golic, Platts, James Alexis, Brancale, Andrea, Deraos, George N., Matsoukas, John M. and Mavromoustakos, Thomas M. 2006. 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. Journal of Medicinal Chemistry 49 (23) , pp. 6683-6691. 10.1021/jm060040z

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Chemistry Pharmacy
Subjects:	Q Science > QD Chemistry R Medicine > RM Therapeutics. Pharmacology
Publisher:	American Chemical Society
ISSN:	0022-2623
Last Modified:	04 Jun 2017 02:54
URI:	http://orca.cf.ac.uk/id/eprint/13582

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