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. ORCID: https://orcid.org/0000-0002-6313-1409, Tselios, Theodore V., Grdadolnik, Simona Golic, Platts, James Alexis ORCID: https://orcid.org/0000-0002-1008-6595, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, 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:	05 Jan 2024 05:49
URI:	https://orca.cardiff.ac.uk/id/eprint/13582

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