NMR and molecular dynamics studies of an autoimmune myelin basic protein peptide and its antagonist - Structural implications for the MHC II (I-A(u))-peptide complex from docking calculations
Φόρτωση...
Ημερομηνία
Συγγραφείς
Tzakos, A. G.
Fuchs, P.
van Nuland, N. A. J.
Troganis, A.
Tselios, T.
Deraos, S.
Matsoukas, J.
Gerothanassis, I. P.
Bonvin, A. M. J. J.
Τίτλος Εφημερίδας
Περιοδικό ISSN
Τίτλος τόμου
Εκδότης
Wiley-Blackwell
Περίληψη
Τύπος
Είδος δημοσίευσης σε συνέδριο
Είδος περιοδικού
peer reviewed
Είδος εκπαιδευτικού υλικού
Όνομα συνεδρίου
Όνομα περιοδικού
European Journal of Biochemistry
Όνομα βιβλίου
Σειρά βιβλίου
Έκδοση βιβλίου
Συμπληρωματικός/δευτερεύων τίτλος
Περιγραφή
Experimental autoimmune encephalomyelitis can be induced in susceptible animals by immunodominant determinants of myelin basic protein (MBP). To characterize the molecular features of antigenic sites important for designing experimental autoimmune encephalomyelitis suppressing molecules, we report structural studies, based on NMR experimental data in conjunction with molecular dynamic simulations, of the potent linear dodecapeptide epitope of guinea pig MBP, Gln74-Lys75-Ser76-Gln77-Arg78-Ser79-Gln80-Asp81-Glu82-Asn83-Pro84-Val85 [MBP(74-85)], and its antagonist analogue Ala81MBP(74-85). The two peptides were studied in both water and Me(2)SO in order to mimic solvent-dependent structural changes in MBP. The agonist MBP(74-85) adopts a compact conformation because of electrostatic interactions of Arg78 with the side chains of Asp81 and Glu82. Arg78 is 'locked' in a well-defined conformation, perpendicular to the peptide backbone which is practically solvent independent. These electrostatic interactions are, however, absent from the antagonist Ala81MBP(74-85), resulting in great flexibility of the side chain of Arg78. Sequence alignment of the two analogues with several species of MBP suggests a critical role for the positively charged residue Arg78, firstly, in the stabilization of the local microdomains (epitopes) of the integral protein, and secondly, in a number of post-translational modifications relevant to multiple sclerosis, such as the conversion of charged arginine residues to uncharged citrullines. Flexible docking calculations on the binding of the MBP(74-85) antigen to the MHC class II receptor site I-A(u) using <smallcapitals>haddock</smallcapitals> indicate that Gln74, Ser76 and Ser79 are MHC II anchor residues. Lys75, Arg78 and Asp81 are prominent, solvent-exposed residues and, thus, may be of importance in the formation of the trimolecular T-cell receptor-MBP(74-85)-MHC II complex.
Περιγραφή
Λέξεις-κλειδιά
conformation, docking, major histocompatibility complex, molecular dynamics, myelin basic epitope, experimental allergic encephalomyelitis, t-cell-receptor, central-nervous-system, amino acid sequence, 3-dimensional structure, monoclonal-antibodies, secondary structure, multiple-sclerosis, crystal-structure, force-field
Θεματική κατηγορία
Παραπομπή
Σύνδεσμος
<Go to ISI>://000223101800012
http://onlinelibrary.wiley.com/store/10.1111/j.1432-1033.2004.04274.x/asset/j.1432-1033.2004.04274.x.pdf?v=1&t=hmn3j9lc&s=86e7172b3097f45c04fcee1fb5fadba12aa5ddec
http://onlinelibrary.wiley.com/store/10.1111/j.1432-1033.2004.04274.x/asset/j.1432-1033.2004.04274.x.pdf?v=1&t=hmn3j9lc&s=86e7172b3097f45c04fcee1fb5fadba12aa5ddec
Γλώσσα
en
Εκδίδον τμήμα/τομέας
Όνομα επιβλέποντος
Εξεταστική επιτροπή
Γενική Περιγραφή / Σχόλια
Ίδρυμα και Σχολή/Τμήμα του υποβάλλοντος
Πανεπιστήμιο Ιωαννίνων. Σχολή Θετικών Επιστημών. Τμήμα Χημείας