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Conformational studies of immunodominant myelin basic protein 1–11 analogues using NMR and molecular modeling

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Abstract

Τwo dimensional nuclear magnetic resonance studies complimented by molecular dynamics simulations were conducted to investigate the conformation of the immunodominant epitope of acetylated myelin basic protein residues 1–11 (Ac-MBP1–11) and its altered peptide ligands, mutated at position 4 to an alanine (Ac-MBP1–11[4A]) or a tyrosine residue (Ac-MBP1–11[4Y]). Conformational analysis of the three analogues indicated that they adopt an extended conformation in DMSO solution as no long distance NOE connectivities were observed and seem to have a similar conformation when bound to the active site of the major histocompatibility complex (MHC II). The interaction of each peptide with MHC class II I–Au was further investigated in order to explore the molecular mechanism of experimental autoimmune encephalomyelitis induction/inhibition in mice. The present findings indicate that the Gln3 residue, which serves as a T-cell receptor (TCR) contact site in the TCR/peptide/I–Au complex, has a different orientation in the mutated analogues especially in the Ac-MBP1–11[4A] peptide. In particular the side chain of Gln3 is not solvent exposed as for the native Ac-MBP1–11 and it is not available for interaction with the TCR.

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Acknowledgments

D. Laimou was supported by the University of Patras (Grant K. Karatheodoris). M. Katsara was supported by the Ministry of Development Secretariat of Research and Technology of Greece (Grant Aus. 005) and Du Pré grant from MSIF. V. Apostolopoulos and E. Lazoura were in part supported by an NH&MRC project grant 223310. In addition, V. Apostolopoulos was supported by NH&MRC of Australia R. Douglas Wright Fellowship (223316). E. Lazoura, M. Katsara and V. Apostolopoulos were located at the Austin Research Institute when the studies were undertaken prior to the merger with the Burnet Institute. Hence, E. L, M. K and V. A. would like to acknowledge the support of the Austin Research Institute.

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Authors and Affiliations

  1. Department of Chemistry, University of Patras, 26500, Patras, Greece

    Despina Laimou, Minos-Timotheos Matsoukas, Spyros N. Deraos, Maria Katsara, John Matsoukas & Theodore V. Tselios

  2. Centre for Immunology, Burnet Institute, Melbourne, VIC, 3004, Australia

    Eliada Lazoura, Maria Katsara & Vasso Apostolopoulos

  3. Department of Biological Applications and Technologies, University of Ioannina, 45110, Ioannina, Greece

    Anastassios N. Troganis

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  1. Despina Laimou
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  2. Eliada Lazoura
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  3. Anastassios N. Troganis
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  4. Minos-Timotheos Matsoukas
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  6. Maria Katsara
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  8. Vasso Apostolopoulos
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  9. Theodore V. Tselios
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Correspondence to Theodore V. Tselios.

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Despina Laimou and Eliada Lazoura contributed equally to this work.

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Laimou, D., Lazoura, E., Troganis, A.N. et al. Conformational studies of immunodominant myelin basic protein 1–11 analogues using NMR and molecular modeling. J Comput Aided Mol Des 25, 1019–1032 (2011). https://doi.org/10.1007/s10822-011-9481-6

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  • DOI: https://doi.org/10.1007/s10822-011-9481-6

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