Molecular dynamics at the receptor level of immunodominant myelin basic protein epitope 87-99 implicated in multiple sclerosis and its antagonists altered peptide ligands: Triggering of immune response

Mantzourani, Efthymia D. ORCID: https://orcid.org/0000-0002-6313-1409, Platts, James Alexis ORCID: https://orcid.org/0000-0002-1008-6595, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, Mavromoustakos, Thomas M. and Tselios, Theodore V. 2007. Molecular dynamics at the receptor level of immunodominant myelin basic protein epitope 87-99 implicated in multiple sclerosis and its antagonists altered peptide ligands: Triggering of immune response. Journal of Molecular Graphics and Modelling 26 (2) , pp. 471-481. 10.1016/j.jmgm.2007.02.004

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Abstract

This work reports molecular dynamics studies at the receptor level of the immunodominant myelin basic protein (MBP) epitope 87–99 implicated in multiple sclerosis, and its antagonists altered peptide ligands (APLs), namely [Arg91, Ala96] MBP87–99 and [Ala91,96] MBP87–99. The interaction of each peptide ligand with the receptor human leukocyte antigen HLA-DR2b was studied, starting from X-ray structure with pdb code: 1ymm. This is the first such study of APL-HLA-DR2b complexes, and hence the first attempt to gain a better understanding of the molecular recognition mechanisms that underlie TCR antagonism by these APLs. The amino acids His88 and Phe89 serve as T-cell receptor (TCR) anchors in the formation of the trimolecular complex TCR-peptide-HLA-DR2b, where the TCR binds in a diagonal, off-centered mode to the peptide-HLA complex. The present findings indicate that these two amino acids have a different orientation in the APLs [Arg91, Ala96] MBP87–99 and [Ala91,96] MBP87–99: His88 and Phe89 remain buried in HLA grooves and are not available for interaction with the TCR. We propose that this different topology could provide a possible mechanism of action for TCR antagonism.

Item Type:	Article
Status:	Published
Schools:	Pharmacy Chemistry
Uncontrolled Keywords:	Molecular dynamics; Peptides; Receptors; Molecular recognition; Altered peptide ligands
Publisher:	Elsevier
ISSN:	1093-3263
Last Modified:	05 Jan 2024 05:56
URI:	https://orca.cardiff.ac.uk/id/eprint/6630

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