A putative bioactive conformation for the altered peptide ligand of myelin basic protein and inhibitor of experimental autoimmune encephalomyelitis [Arg91, Ala96] MBP87–99

Mantzourani, Efi; Tselios, Theodore; Grdadolnik, Simona Golič; Brancale, Andrea; Platts, James Alexis; Matsoukas, John; Mavromoustakos, Thomas

doi:10.1016/j.jmgm.2005.09.010

Cited by 18 publications

(16 citation statements)

References 46 publications

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“…This may also explain their antagonistic versus agonistic activity. Such differences in the binding motifs between linear and cyclic agonists and antagonists analogues of MBP 87-99 epitope were also shown in our previous work [19][20][21][22][23][24][25][26].…”

Section: Resultssupporting

confidence: 83%

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Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

Potamitis

Matsoukas

Tselios

et al. 2011

J Comput Aided Mol Des

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The two new synthetic analogues of the MBP(83-99) epitope substituted at Lys(91) (primary TCR contact) with Phe [MBP(83-99) (Phe(91))] or Tyr [MBP(83-99) (Tyr(91))], have been structurally elucidated using 1D and 2D high resolution NMR studies. The conformational analysis of the two altered peptide ligands (APLs) has been performed and showed that they adopt a linear and extended conformation which is in agreement with the structural requirements of the peptides that interact with the HLA-DR2 and TCR receptors. In addition, Molecular Dynamics (MD) simulations of the two analogues in complex with HLA-DR2 (DRA, DRB1*1501) and TCR were performed. Similarities and differences of the binding motif of the two analogues were observed which provide a possible explanation of their biological activity. Their differences in the binding mode in comparison with the MBP(83-99) epitope may also explain their antagonistic versus agonistic activity. The obtained results clearly indicate that substitutions in crucial amino acids (TCR contacts) in combination with the specific conformational characteristics of the MBP(83-99) immunodominant epitope lead to an alteration of their biological activity. These results make the rational drug design intriguing since the biological activity is very sensitive to the substitution and conformation of the mutated MBP epitopes.

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Section: Resultssupporting

confidence: 83%

“…NMR spectroscopy is coupled with MD simulations to study the binding motif of the altered peptide epitopes of MBP 83-99 with HLA-DR2 [19][20][21][22][23][24][25][26][27][28][29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

Potamitis

Matsoukas

Tselios

et al. 2011

J Comput Aided Mol Des

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“…It is shown that both human autoimmune TCRs primarily recognize the Nterminal residues. We used the HLA-DR2b receptor to study the binding of two linear APLs, [ -DR2b complexes, with 2ns simulation time, using as an initial conformation for the peptides the putative active one as proposed by our earlier studies [30,31]. The X-ray structure of the peptide -HLA-DR2b complex was subjected to the same simulation.…”

Section: Resultsmentioning

confidence: 99%

“…In previous work [30] we proposed an active conformation of [Arg 91 , Ala 96 ] MBP 87-99 using a combination of NMR and MD studies. The proposed bioactive conformation was used as the starting point of MD simulation of the [Arg 91 , Ala 96 ] MBP 87-99 -HLA-DR2b complex.…”

Section: Molecular Dynamics Of [Arg 91 Ala 96 ] Mbp 87-99 Complexedmentioning

confidence: 99%

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

Platts

Brancale

et al. 2007

Journal of Molecular Graphics and Modelling

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“…It is necessary to study a whole range of pMHC interactions, comparing MD simulations with in vivo data to determine the generalizability of molecular mechanisms through which conformational changes in MHC molecules are translated into alterations in T cell proliferation and function. Nevertheless, well-tailored MD simulations that correlate with functional immunological outcomes [22], [23], [24], [25], [26], [27], [28], [29] may be useful for designing therapeutic APLs to treat diseases such as multiple sclerosis [30], [31], [32].…”

Section: Discussionmentioning

confidence: 99%

A Comparative Approach Linking Molecular Dynamics of Altered Peptide Ligands and MHC with In Vivo Immune Responses

et al. 2010

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BackgroundThe recognition of peptide in the context of MHC by T lymphocytes is a critical step in the initiation of an adaptive immune response. However, the molecular nature of the interaction between peptide and MHC and how it influences T cell responsiveness is not fully understood.ResultsWe analyzed the immunological consequences of the interaction of MHC class II (I-Au) restricted 11-mer peptides of myelin basic protein with amino acid substitutions at position 4. These mutant peptides differ in MHC binding affinity, CD4+ T cell priming, and alter the severity of peptide-induced experimental allergic encephalomyelitis. Using molecular dynamics, a computational method of quantifying intrinsic movements of proteins at high resolution, we investigated conformational changes in MHC upon peptide binding. We found that irrespective of peptide binding affinity, MHC deformation appears to influence costimulation, which then leads to effective T cell priming and disease induction. Although this study compares in vivo and molecular dynamics results for three altered peptide ligands, further investigation with similar complexes is essential to determine whether spatial rearrangement of peptide-MHC and costimulatory complexes is an additional level of T cell regulation.

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A putative bioactive conformation for the altered peptide ligand of myelin basic protein and inhibitor of experimental autoimmune encephalomyelitis [Arg91, Ala96] MBP87–99

Cited by 18 publications

References 46 publications

Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

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

A Comparative Approach Linking Molecular Dynamics of Altered Peptide Ligands and MHC with In Vivo Immune Responses

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